Bernard–Soulier Syndrome and Inherited Giant Platelet Thrombocytopenias

An inherited platelet disorder caused by quantitative or qualitative deficiency of the glycoprotein complex GPIb-IX-V, the platelet receptor for von Willebrand factor, with macrothrombocytopenia, absent or reduced ristocetin-induced agglutination and mucocutaneous bleeding; it includes the biallelic autosomal recessive forms, the monoallelic autosomal dominant forms and the class of inherited macrothrombocytopenias that make up its differential diagnosis.

Literature and regulatory information updated: 27 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description

In 1948, the French haematologists Jean Bernard and Jean-Pierre Soulier described a young male patient with severe bleeding, prolonged bleeding time and thrombocytopenia with very large platelets, and named the condition “congenital haemorrhagiparous thrombocytic dystrophy” [1, 2]. The index patient had repeated bleeding throughout his life and died at the age of 28 of a cerebral haemorrhage after a physical assault [30]. The cases published over the following decades were mostly of autosomal recessive transmission, frequently in children of consanguineous couples [1]. The classic description combined prolonged bleeding time, unusually large platelets, thrombocytopenia and reduced prothrombin consumption, which reflects the reduced capacity of the platelets to support thrombin generation [3, 31]. Among the first family descriptions, Cullum and colleagues reported in 1967 two brothers from a consanguineous family of Sicilian origin with thrombocytopenia, abnormally large platelets, prolonged bleeding time and normal clot retraction; the five children of the two brothers had abnormal platelet morphology, and the authors interpreted the brothers as homozygous and the relatives with abnormal platelets without bleeding as heterozygous [8]. The second patient described by Jean Bernard's group, published in 1957, was restudied in 2002: he had a homozygous variant in the signal peptide of GPIX (Leu7Pro; NM_000174.5:c.20T>C p.(Leu7Pro) [32]), at the time the only known defect of the leader sequence in BSS [19].

1.2. From the missing glycoprotein to the gene

In 1969, Grøttum and Solum observed reduced electrophoretic mobility of BSS platelets, attributed to a marked reduction in membrane sialic acid, and in 1974 Weiss and colleagues demonstrated defective platelet adhesion to the subendothelium and proposed the absence of a VWF receptor [8]. In 1975, Nurden and Caen showed that the platelets of these patients had only traces of a membrane glycoprotein of about 155 kDa and lacked one of the main surface glycoprotein complexes, later identified as the set of subunits of the GPIb-IX-V complex [8, 31]. In 1978 it was found that BSS platelets lacked the receptor for quinine- and quinidine-dependent antibodies, and in 1980 Hagen and colleagues confirmed the VWF receptor defect and showed that heterozygotes (for example, the parents) have reduced glycoprotein I without impaired platelet function or bleeding [8]. In 1983, a whole-blood assay with monoclonal antibodies began to identify the absence of GPIb in BSS and of GPIIb/IIIa in Glanzmann thrombasthenia [8]. The first molecular variant was published in 1990: a nonsense variant in the coding sequence of GPIbα [33], designated Trp343Ter in OMIM (historical numbering, = NM_000173.7:c.1077G>A p.(Trp359Ter)) [32]; the patient's mother and two of his four children had the truncated chain alongside the normal protein [13]. The first variants in the other genes followed: in GP9, compound heterozygosity Asp21Gly/Asn45Ser (mature numbering, = NM_000174.5:c.110A>G p.(Asp37Gly) and c.182A>G p.(Asn61Ser)) in three siblings (1993); in GP1BB, compound heterozygosity Tyr88Cys/Ala108Pro (mature numbering, = NM_000407.5:c.338A>G p.(Tyr113Cys) and c.397G>C p.(Ala133Pro)) in two Japanese sisters (1997), the promoter variant associated with the 22q11.2 deletion (1996) and the first homozygosity, for a nonsense variant at codon 21 (2000; = NM_000407.5:c.137G>A p.(Trp46Ter)) [8, 18, 19]. In 2006, the Orphanet Journal of Rare Diseases review counted 47 genetic defects (20 in GP1BA, 16 in GP1BB and 11 in GP9) and none in GP5 [1]; before the 2017 NIHR BioResource study, 45, 39 and 28 variants had been described, respectively [10]. In 2014, the International Consortium for the Study of BSS gathered 211 genotyped families, with 112 different variants [20].

1.3. From the recessive model to the monoallelic form

Until electronic counters became widespread in the 1990s, platelet counts were performed under the microscope and only in patients with a bleeding diathesis, so only the severe forms of inherited thrombocytopenia were recognised; the 1990 edition of Williams Textbook of Hematology described four inherited thrombocytopenias and classified BSS as recessive [23]. The first family with autosomal dominant BSS was published in 1992 by Miller and colleagues: five patients in two generations, with a moderate bleeding tendency, thrombocytopenia and increased MPV, heterozygous for the Leu57Phe variant (historical numbering, = NM_000173.7:c.217C>T p.(Leu73Phe)) of GP1BA in the leucine-rich repeat [9, 13]. In 2001, Savoia and colleagues, after establishing linkage to 17p in two large Italian families, showed that Italian autosomal dominant macrothrombocytopenia, formerly called “Mediterranean macrothrombocytopenia”, was associated in 6 of 12 families with the heterozygous GP1BA variant known as Ala156Val (historical numbering, = NM_000173.7:c.515C>T p.(Ala172Val); Bolzano variant) [32, 34]. In 2012, the same network described 103 patients from 42 families with this variant and proposed the term “monoallelic dominant BSS” to distinguish this mild form from asymptomatic carriers of recessive variants and from the severe biallelic form [23]. In 2017, analysis of more than 1000 genomes from the NIHR BioResource associated rare monoallelic GP1BB variants with autosomal dominant macrothrombocytopenia [10], and in 2021 the Copenhagen variant of GP1BA proved to be the most frequent cause of inherited thrombocytopenia in a Danish cohort [24].

1.4. Nomenclature and classifications in use

The literature uses three complementary classifications. The classification by inheritance, adopted by GeneReviews and by the 2025 review, distinguishes biallelic BSS (OMIM 231200, autosomal recessive, AR, due to homozygosity or compound heterozygosity in GP1BA, GP1BB or GP9) and monoallelic BSS (OMIM 153670, autosomal dominant, AD, described in GP1BA and GP1BB) [4, 21]. The classification by gene, used by OMIM and by gene therapy groups, designates the recessive form of GP1BA as type A1, the dominant form of GP1BA as type A2, the GP1BB form as type B and the GP9 form as type C [3, 7]. The biochemical classification separates classic BSS, with markedly reduced or absent expression of the complex, from variant BSS, with an expressed complex that is unable to bind von Willebrand factor (VWF) [1, 35]. OMIM places BSS in a series of platelet-type bleeding disorders numbered BDPLT1 to BDPLT25, in which BSS is BDPLT1, platelet-type von Willebrand disease BDPLT3, grey platelet syndrome BDPLT4 and MYH9-RD BDPLT6; several entries of the series correspond to macrothrombocytopenias in the differential diagnosis (BDPLT15 due to ACTN1, BDPLT16 due to ITGA2B, BDPLT17 due to GFI1B, BDPLT19 due to PRKACG, BDPLT20 due to SLFN14, BDPLT21 due to FLI1 and BDPLT24 due to ITGB3) [8]. An Iranian report from 2026 also mentions a classification into three types according to residual GPIb-IX-V expression, with type 1 (<5% expression) as the most severe, without indicating the primary source [36].

1.5. Scope of the article

This article covers biallelic and monoallelic BSS and the class of inherited thrombocytopenias with large or giant platelets, because the first clinical problem is to distinguish these entities from one another and from immune thrombocytopenia (ITP). Orphanet groups these conditions under “Isolated hereditary giant platelet disorder” (ORPHA:220452), which includes MYH9-related disease (MYH9-RD, ORPHA:182050), autosomal dominant macrothrombocytopenia (ORPHA:140957) and severe autosomal recessive macrothrombocytopenia (ORPHA:438207) [6, 37–39]. The 22q11.2 deletion, which removes one allele of GP1BB, is discussed for its platelet consequences; platelet-type von Willebrand disease, an allelic gain-of-function disorder of GP1BA, and Glanzmann thrombasthenia, the other severe glycoprotein platelet disorder, are part of the differential diagnosis [3, 22, 30].

2. Molecular Genetics and Pathophysiology

2.1. The GPIb-IX-V complex

The GPIb-IX-V complex is formed by four transmembrane proteins of the leucine-rich repeat family, whose expression is restricted to megakaryocytes and platelets: GPIbα (135 kDa, which contains the VWF binding site), GPIbβ (26 kDa), GPIX (20 kDa) and GPV (82 kDa) [1]. GPIbα is linked by disulphide bonds to GPIbβ and associates non-covalently with GPIX and GPV [3, 40]. The reported stoichiometry has varied with the methods: a GPIbα:GPIbβ:GPIX:GPV ratio of 2:2:2:1 in older studies and of 2:4:2:1 after it was shown that each GPIbα binds two GPIbβ [31, 35]. GPIbα, GPIbβ and GPIX are all required for efficient biosynthesis of the complex, which is assembled in the endoplasmic reticulum and the Golgi apparatus; the absence of any one of them drastically reduces surface expression of the others. GPV associates more loosely, and its absence prevents neither expression of the complex nor VWF binding [1, 35]. In each gene the coding sequence is contained in a single exon, except for GP1BB, which has a 10 bp intron immediately after the initiation codon [1].

2.2. Functions of the complex and consequences of its absence

The main function of the complex is the initial adhesion of platelets to VWF bound to exposed subendothelial collagen, under high-shear conditions such as those of the arterial circulation (shear rates above 800 s⁻¹) [16, 31]. The 282-residue N-terminal domain of GPIbα also binds thrombospondin, P-selectin from the endothelium and activated platelets, the leucocyte integrin αMβ2 (Mac-1), α-thrombin, factors XI and XII and high-molecular-weight kininogen; the cytoplasmic tail binds filamin A, calmodulin, 14-3-3ζ and the p85 subunit of phosphatidylinositol 3-kinase, and the complex co-associates with GPVI, the collagen receptor [31, 40]. VWF binding triggers a signalling cascade, whose first identified effector is the kinase Lyn, leading to activation of integrin αIIbβ3 [31].

Each component of the laboratory phenotype has a mechanistic explanation. Absent or markedly reduced agglutination with ristocetin results from the absence of the VWF binding site on GPIbα. The prolonged bleeding time reflects the combination of this defect with the low count and reduced thrombin production. Reduced thrombin generation, classically measured as reduced prothrombin consumption, is attributed to the absence of the binding site for factors XI and XII on the platelet. The reduced response to low doses of α-thrombin is due to loss of the potentiation of protease-activated receptor 1 (PAR-1) activation by thrombin bound to GPIbα [1, 31]. The large platelets and low count are attributed to loss of the binding of the GPIbα tail to filamin A, which anchors the complex to the membrane skeleton; in mice lacking GPIbα, expression of a GPIbα in which almost the entire extracellular domain was replaced by a domain of the interleukin 4 receptor, but with a normal cytoplasmic tail, largely corrects the macrothrombocytopenia [31]. The same loss explains the increased membrane deformability of BSS platelets [31]. The complex is required for normal megakaryocyte maturation, which makes BSS a disease with a simultaneously quantitative and functional defect [3, 40].

2.3. The genes

Sources: [1, 3, 15–17, 20, 35]. The 2006 review placed GP1BA at 17p12; current databases (HGNC, GeneGuidance, OMIM) and a 2026 report give 17p13.2 [1, 3, 13, 41].

The complementary DNA of GPIbα encodes a protein of 610 amino acids, of about 145 kDa, comprising an extracytoplasmic domain of leucine-rich repeats (a 24-amino-acid motif with 7 conserved leucines), a 29-amino-acid transmembrane domain and a 100-amino-acid intracellular domain; the region between Thr536 and Phe568 of the cytoplasmic tail participates in binding to actin-binding protein (filamin), which anchors the complex to the membrane skeleton [13]. Cleavage of GPIbα by trypsin or calpain releases a soluble, heavily glycosylated N-terminal fragment, glycocalicin, which contains the thrombin binding site; the plasma concentration of glycocalicin has been proposed as a marker of platelet turnover, low in marrow suppression and normal or raised in accelerated peripheral destruction [13]. GPIbβ is synthesised as a 206-amino-acid precursor from a messenger RNA of about 1.0 kb expressed in megakaryocytes, with a single leucine-rich repeat, a 25-amino-acid transmembrane segment and a 34-amino-acid intracellular segment; a 3.5 kb transcript detected in endothelium and other cell lines results from an imperfect polyadenylation sequence in the neighbouring upstream gene (SEPT5), which uses the GP1BB polyadenylation site [18]. GPIX has 165 amino acids (about 17 kDa), with a single leucine-rich repeat, an extracellular region of 134 residues and an intracytoplasmic region of only 6 residues, and forms a 1:1 non-covalent complex with GPIb [19].

2.4. Variant spectrum in the biallelic forms

Variants fall into three classes: missense variants or small in-frame deletions, which rarely produce a dysfunctional receptor with normal or slightly reduced expression and more often an unstable complex with markedly reduced expression; nonsense variants, which produce truncated subunits without a transmembrane domain; and frameshift variants, which generate a novel polypeptide terminated by a premature stop codon [1, 31]. There are also variants in the signal peptides of GPIbβ and GPIX [31]. In the international series of 211 families, GP9 was the affected gene in 44%, GP1BA in 28% and GP1BB in 28%; 85% of the probands were homozygous, there were founder effects in some geographical areas and most variants prevented membrane expression of the complex, while a minority affected only the interaction with VWF [20]. Most variants are private, found in a single family [1, 16].

OMIM selects a set of historically relevant variants, in the numbering of the original papers (mature protein in the case of GP9 and of most GP1BA variants); the correspondence with the MANE transcript given in parentheses was obtained from ClinVar using the dbSNP identifier of each OMIM entry [13, 18, 19, 32].

Structural modelling in the Pavia series showed how missense variants destabilise the protein. In GPIbα (NM_000173.7), p.Asn126Asp (c.376A>G in ClinVar) affects the conserved asparagine of the leucine-rich repeat consensus (LxxLxLxxNxL), buried in the hydrophobic core, and p.Cys225Ser (the paper does not give the nucleotide change; ClinVar records c.673T>A and c.674G>C) destroys the Cys225–Cys264 disulphide bond. In GPIX (NM_000174.5), the variants of Cys24 (CPXPCXC motif; c.70T>C p.(Cys24Arg) and c.72T>G p.(Cys24Trp)), Leu63 (c.188T>C), Phe71 (c.212T>C p.(Phe71Ser), = Phe55Ser in OMIM) and Tyr95 (c.284A>G p.(Tyr95Cys)) affect residues buried in the hydrophobic core; p.Leu63Pro prevents the reversal of chain direction and was considered the most destabilising [35]. The protein notation of these residues follows the numbering of each paper: the GPIX variant designated p.Cys24Arg in the Pavia series corresponds to the designation C8R in the accompanying editorial, which uses the numbering of the mature protein [31, 35].

2.5. Recurrent and founder variants

Conversions between the historical numbering (mature protein, without the 16 amino acids of the signal peptide) and current HGVS numbering (Human Genome Variation Society) were confirmed in VariantValidator and ClinVar.

Source of the conversions: [17, 32]. Among the other monoallelic GP1BA variants, the Pavia papers cite p.Asn41His, p.Tyr54Asp and p.Leu57Phe (2012 series) and p.Leu73Phe (2011 series), without stating the numbering convention or the transcript; p.Asn41His and p.Tyr54Asp were not normalised, and the OMIM Leu57Phe corresponds, through dbSNP rs121908063, to NM_000173.7:c.217C>T p.(Leu73Phe), so the two Pavia designations refer to the same residue in different numberings (mature and full-length) [23, 32, 35]. Barozzi and colleagues described in 2023 a GP1BB variant designated “c.179C>T” as the second cause of monoallelic BSS in Italy, after Bolzano; this notation is not compatible with the reference sequence NM_000407.5, which has T at position c.179, and ClinVar records NM_000407.5:c.179T>C p.(Leu60Pro) (VCV 1695035, likely pathogenic, single submitter), without the sources consulted allowing the correspondence between the two to be established [17, 32, 44]. In a 2026 Iranian series of eight patients, six causal variants were found, three of them novel (GP9 c.151_154delGCCC and c.357delT; GP1BA c.522C>A), in addition to GP1BB c.47T>C and c.390delC and GP1BA c.624_625insT in three patients; the abstract does not give the transcripts [42].

2.6. Mechanism of the monoallelic forms

Not all heterozygous variants produce a phenotype. The 22q11.2 microdeletions, which remove one allele of GP1BB, reduce surface expression of the complex to about 50%, but, according to the Italian series, in most cases cause neither thrombocytopenia nor macrocytosis; it follows that 50% expression is sufficient for normal megakaryopoiesis, and that some GP1BA variants (Bolzano, p.Asn41His, p.Tyr54Asp and p.Leu57Phe, in the paper's mature numbering; the last = NM_000173.7:p.(Leu73Phe)) exert a dominant effect that alters platelet count and size even with half of the normal protein [23]. These variants allow assembly of the complex in the membrane but prevent GPIbα from binding VWF [23, 35]. For the Bolzano variant, the sources differ on expression: the 2011 editorial describes essentially normal levels of a dysfunctional complex, whereas flow cytometry in 37 patients of the 2012 series showed a significant reduction of all components of the complex, to about 50% of control [23, 31]. For GP1BB, the NIHR BioResource proposed that the unequal stoichiometry of the complex (four GPIbβ per two GPIbα) explains a dominant negative effect of missense variants, and that haploinsufficiency explains the variants that abolish the initiation codon [10]. In the Danish series, the platelets of carriers of the Copenhagen variant formed a heterogeneous population, with large platelets (mean diameter above 3.9 µm) and elongated platelets, partial reduction of GPIb on immunofluorescence and a CD42b/CD41a ratio of 0.40–0.67 [24]. Serum thrombopoietin was not reduced: in the Bolzano series, the mean was about twice that of 50 controls (24.6 ± 21.9 vs 14 ± 10.8 pg/mL), which indicates that megakaryocyte mass is not reduced; in the Danish series there was no difference from healthy relatives (median 16.5 vs 17 AU/mL) [23, 24].

2.7. GP1BB and the 22q11.2 deletion

Because GP1BB lies at 22q11.21, every patient with a 22q11.2 deletion is an obligate BSS carrier; a pathogenic GP1BB variant on the non-deleted allele produces BSS through hemizygosity, with a combined phenotype of BSS and DiGeorge/velocardiofacial syndrome [1, 22, 45]. The first patient described (1995–1996) was a boy with velocardiofacial syndrome who had abnormal bleeding at cardiac catheterisation at 18 months and at circumcision at 3 years, easy bruising and epistaxis; he had large platelets, reduced ristocetin aggregation, reduced GPIbα and absent GPIbβ, and on the non-deleted allele a GP1BB promoter variant (−133C>G) that disrupts a GATA binding site [8, 18]. The authors had initially considered that GP1BB hemizygosity was not sufficient to cause BSS, as this was the first case described in association with velocardiofacial syndrome [18]. Expression of the complex is reduced to about 50% in the isolated deletion, with reduced ristocetin agglutination [35]. As for the count, the sources differ: the Italian series states that most of these patients have neither thrombocytopenia nor macrocytosis [23], whereas a 2025 review describes mild macrothrombocytopenia as frequent, presumably attributed to the loss of one GP1BB allele, with contributions from defective megakaryopoiesis, vasculogenesis and modifiers outside the region [46]. Even after excluding ITP, the mean count in these patients is about 70% of that of controls [47]. Homozygous deletion of GP1BB and the contiguous gene SEPT5, inherited from heterozygous parents, has also been described in a 4-year-old boy with severe BSS, a platelet secretion defect, polymicrogyria and developmental delay [48].

2.8. Genotype–phenotype correlations

In the single-centre Pavia series (13 patients from 10 families, all homozygous), GPIbα was always below 10% of control and bleeding severity did not correlate with the count, which was always moderate (34–82 × 10⁹/L by microscopy), nor with GPIbα expression [35]. Nevertheless, all 5 patients with GP9 variants at residue Cys24 (NM_000174.5:c.70T>C p.(Cys24Arg) or c.72T>G p.(Cys24Trp)) and the patient with c.284A>G p.(Tyr95Cys) had mild bleeding (World Health Organization, WHO, grade 2), whereas the 3 patients with GP1BA or GP1BB variants and the carriers of GP9 c.188T>C p.(Leu63Pro), c.212T>C p.(Phe71Ser) and c.442dup p.(Val148GlyfsTer67) had grade 3 or 4 bleeding; the GP1BA p.Cys225Ser and GP9 p.Phe71Ser variants were also associated with a severe phenotype in other reports [35]. In a Swiss family, four homozygotes for GP9 Asn45Ser (mature numbering, = NM_000174.5:c.182A>G p.(Asn61Ser)) had variable bleeding risk [31]. The editorial accompanying the series attributed part of the variability to other haemostasis genes, by analogy with the influence of genetic background in murine models [31].

Heterozygotes for recessive variants are generally asymptomatic, with a normal count (151–380 × 10⁹/L in the 7 obligate carriers from Pavia) and platelet diameter at the upper limit of normal; the exception was the 2 carriers of GP9 NM_000174.5:c.188T>C p.(Leu63Pro), with expression of the complex of about 50% and reduced aggregation (14–45%) with ristocetin at 1.5 mg/mL [35]. Some recessive variants, such as GPIbβ p.Tyr88Cys (mature numbering, = NM_000407.5:c.338A>G p.(Tyr113Cys)), produce larger platelets in carriers [23]. In the family with the GP9 Leu40Pro variant (mature numbering, = NM_000174.5:c.167T>C p.(Leu56Pro)), heterozygotes had mild bleeding and/or giant platelets, whereas homozygotes had severe bleeding [19]. Compound heterozygosity GP1BB Tyr88Cys/Ala108Pro (mature numbering) produced giant platelets without thrombocytopenia, which led the authors to propose a continuous spectrum, from the normal phenotype to the isolated giant platelet disorder and full BSS; OMIM records this form as “isolated giant platelet disorder” within entry 231200 [8, 18].

2.9. Allelic disorders and modifiers

Gain-of-function GP1BA variants increase the affinity of GPIbα for VWF: platelets bind circulating VWF, and the platelets and high-molecular-weight multimers are cleared, which produces platelet-type von Willebrand disease (OMIM 177820), with bleeding, not thrombosis [3]. Nine variants have been described; in 2006 three missense variants in a disulphide loop adjacent to the leucine-rich repeat domain and a 9-amino-acid deletion in the macroglycopeptide were known [1, 3]. The structural mechanism, historically attributed to the “beta-switch” region in an extended β-hairpin conformation, is now explained by a conformation that destabilises the compact triangular form of the R-loop, the VWF binding region [3]. The missense polymorphism that defines the HPA-2 alloantigen (rs6065, Thr145Met in mature numbering; NM_000173.7:c.482C>T p.(Thr161Met), benign in ClinVar [32]) alters neither the expression nor the function of the complex [1, 23], and Orphanet lists GP1BA among the candidate genes studied in fetal and neonatal alloimmune thrombocytopenia (ORPHA:853) [3]. According to OMIM, the same substitution corresponds to Thr161Met in the numbering of the full-length protein; the Met145 allele (HPA-2b, also designated Sib(a) or Ko(a)) has a frequency of 0.074 in Europeans and 0.136 in the Japanese population, and antibodies against it have been implicated in fetomaternal alloimmune thrombocytopenia and in transfusion refractoriness, including in a Japanese patient receiving HLA-matched platelets [13]. There are platelet alloantigens on the other subunits too: the GPIbβ Gly15Glu variant (published designation, in mature protein numbering) defines HPA-12bw, and the GPIX Pro123Leu variant (NM_000174.5:c.368C>T p.(Pro123Leu), benign in ClinVar; Pro107Leu in the cleaved protein), designated Cab4b, caused severe fetomaternal alloimmune thrombocytopenia with intracranial haemorrhage in one family [18, 19]. Other GP1BA polymorphisms have reported associations outside primary haemostasis: the T/C polymorphism at position −5 of the Kozak context, whose C allele increases surface expression of the complex, was not associated with coronary disease in a Japanese and Korean case–control study, but the heterozygous genotype was more frequent in Australian patients with a first ischaemic stroke (32.2% vs 22.8%); and the B allele of the VNTR was associated with non-arteritic anterior ischaemic optic neuropathy (OR 4.25; 95% CI 1.67–10.82), with involvement of the second eye in 9 of 16 carriers (56.3%) versus 17 of 72 non-carriers (23.6%) [13]. These associations come from isolated association studies and do not alter the management of BSS. Among the modifiers studied, the common β1-tubulin Gln43Pro variant (TUBB1; NM_030773.4:c.128A>C p.(Gln43Pro) [32]), associated with changes in platelet shape, did not modify the count, diameter or bleeding score in 22 homozygotes and 81 heterozygotes with the Bolzano variant [23].

2.10. Experimental models

There are murine models with deletion of GPIbα or GPIbβ [1]. The Gp1ba knockout mouse (2000) reproduces the cardinal features of human BSS, and transgenic expression of human GPIbα in platelets corrects the phenotype [8]. The Gp1bb knockout mouse has macrothrombocytopenia, severe bleeding and enlarged α-granules, with Sept5 protein increased 2- to 3-fold in megakaryocytes, probably because the deletion altered expression of the neighbouring gene Sept5 [8, 18]. Deletion of Gp9 in the mouse causes thrombocytopenia with increased platelet volume [19]. In mice whose GPIbα has the extracellular domain replaced by that of the interleukin 4 receptor, platelet adhesion to injured arteries and arterial thrombus formation were practically abolished, which indicates that GPIbα is required for platelet recruitment under arterial flow [13]. Lentiviral rescue of GPIbβ-deficient mice restored the complex in 97% of platelets, VWF binding and the bleeding time, and attenuated the macrothrombocytopenia; deletions in the intracellular domain of GPIbβ showed that the 150–160 region is required for expression (43% reduction when deleted) and that the 159–170 region modulates arterial thrombosis [49]. These models support the gene therapy approaches described in section 7.

3. Clinical Spectrum and Manifestations by System

3.1. Bleeding pattern of the biallelic form

Biallelic BSS is a lifelong mucocutaneous bleeding disorder. Bleeding usually begins soon after birth or in early childhood, with purpura, epistaxis, gum bleeding and, in women, menorrhagia; gastrointestinal bleeding and haematuria are less frequent, and large haematomas are very rare [1]. Severe episodes are concentrated around trauma, surgery (tonsillectomy, appendicectomy, splenectomy), dental extractions and menstruation, with variable severity and frequency between patients [1, 16]. Bleeding is disproportionate to the count because the platelets, in addition to being scarce, are dysfunctional [3, 35]. The bleeding time may exceed 20 minutes, and thrombocytopenia may or may not be present [8]. The bleeding tendency may lessen with age without any change in the thrombocytopenia, as in the Irish patient homozygous for a GP1BB nonsense variant, whose spontaneous bleeding ceased at around 20 years of age [18]. The European patient association describes haemarthroses and deep muscle haematomas as uncommon [50].

3.2. Haematological findings

The constant finding is a reduced number of very large, round platelets, with a mean volume of 11–16 fL and a diameter of 4–10 µm, close to the size of a lymphocyte; the count is typically between 20 and 100 × 10⁹/L, and the bleeding time is moderately (5–10 min) to severely (>20 min) prolonged [1, 16]. In the Pavia series, the microscopic count ranged from 34 to 82 × 10⁹/L and the mean diameter from 3.7 to 5.7 µm; the impedance counter always gave lower counts and never calculated the mean platelet volume (MPV) [35]. Chronic iron deficiency is the main secondary haematological consequence: in the 2026 Mauritanian case, haemoglobin was 5.2 g/dL at 14 years and 7 g/dL at 32 years, with persistent microcytic anaemia [41].

3.3. Cohorts with quantitative data on the biallelic form

The ISTH-BAT (International Society on Thrombosis and Haemostasis Bleeding Assessment Tool) is the ISTH standardised bleeding history questionnaire [4]. The figures from the Indian cohort refer to patients with irregular access to treatment and cannot be read either as untreated natural history or as the history of the treated disease in reference centres.

3.4. Monoallelic form

Monoallelic BSS is characterised by mild macrothrombocytopenia, often asymptomatic and identified late; when bleeding occurs, it is mild (epistaxis, gum bleeding, menorrhagia, easy bruising, prolonged bleeding after dental surgery) [3, 21]. In the Italian Bolzano variant series (103 patients from 42 families, 53 women and 50 men, mean age 33 years, 1–93), 41.7% had recurrent spontaneous bleeding and 58.2% had no bleeding history; none had abnormal bleeding at dental extractions or surgery. The severe episodes were one rectal bleed requiring platelet transfusion, one post-traumatic cerebral haemorrhage, two episodes of epistaxis requiring medical intervention and one postpartum haemorrhage requiring surgical intervention. The mean count was 81 × 10⁹/L, with only 18 patients below 50 × 10⁹/L, and the mean platelet diameter was 50% greater than that of controls; bleeding did not correlate with any laboratory parameter. Thirteen patients had been diagnosed with ITP and five treated with corticosteroids, intravenous immunoglobulin or splenectomy [23]. In the Copenhagen cohort, the 14 probands with monoallelic BSS had counts of 44–128 × 10⁹/L, the ISTH-BAT was significant in only 2, and 4 had been diagnosed with ITP, two of them treated with immunosuppressants during pregnancy [24]. OMIM describes type A2 BSS as chronic macrothrombocytopenia with mild or absent symptoms, normal platelet function and a normal number of megakaryocytes, the latter documented in the marrow of members of three of the six Italian families of 2001 [9]. In the 1992 family with the Leu57Phe variant (p.(Leu73Phe) in NM_000173.7), the proband was 13 years old and was referred for thrombocytopenia detected before dental extractions, with frequent epistaxis, one episode requiring admission; the mother had a long bleeding history, and one of the affected members had an essentially negative bleeding history [13]. In the 18 probands with monoallelic GP1BB variants from the NIHR BioResource, the count was 107.9 × 10⁹/L (47–172) and the MPV 12.74 fL (10.7–14.3) [10].

3.5. Manifestations by age

In the newborn and infant, biallelic BSS may present with purpura and mucosal bleeding; one of the Kuwaiti siblings of 2025 was diagnosed at 6 weeks because of thrombocytopenia with hyperbilirubinaemia, and the Mauritanian patient had epistaxis from 6 months of age [41, 54]. In children, epistaxis, gum bleeding and bleeding after falls, extractions and tonsillectomy predominate [1]. In adolescent girls, menarche is a period of risk: in the Mauritanian case it worsened the anaemia and required transfusions, and in the Pavia series one episode of menorrhagia required uterine tamponade [35, 41]. In adulthood, the monoallelic form is often discovered on a routine blood count or before surgery, and the biallelic form exposes the patient to the cumulative consequences of transfusion, such as alloimmunisation [23, 55].

3.6. Pregnancy

In the 2010 systematic review (16 papers, all case reports; 30 pregnancies in 18 women), there was primary postpartum haemorrhage in 33% and secondary in 40%, blood transfusion in 15 pregnancies, 2 emergency hysterectomies, alloimmune thrombocytopenia in 6 newborns, 1 intrauterine death and 1 neonatal death [56]. In the 2023 review (51 deliveries published up to April 2022), postpartum haemorrhage occurred in 52.9% (27/51), delayed in 35.3% and early in 31.4%; there was severe thrombocytopenia in 49% (25/51), antepartum haemorrhage in 11.8% and caesarean section in 64.7%; postpartum haemorrhage was more frequent after vaginal delivery and less frequent with peripartum prophylaxis [57]. A 2026 review estimates antenatal complications in about two thirds of pregnancies, severe thrombocytopenia being the most frequent [58]. In the monoallelic form, the data are favourable: 19 Italian women had 32 deliveries without transfusion or excessive bleeding, and six Danish women had 13 deliveries without bleeding complications [23, 24]. The 2018 British review compares the 2010 systematic review with the BSS subgroup of the 2014 European study: in the biallelic form (30 deliveries in 18 women), platelet transfusion before delivery was used in 28% versus 53% in the earlier literature, caesarean section in 38% versus 53%, excessive bleeding occurred in 3 of 21 women (14.3%) versus 18 of 30 pregnancies (60%), and blood transfusion in 1 of 21 (4.8%) versus 15 of 30 (50%); in the monoallelic form, 10 of 39 pregnancies (26%) ended in caesarean section, none received prophylactic platelets, 5 (12.8%) had excessive bleeding and 1 (2.6%) needed transfusion [30]. The authors attribute the difference to a milder prior bleeding phenotype in the 2014 study, to self-selection of women with severe bleeding who avoided pregnancy and to publication bias towards case reports with worse outcomes, and conclude that the 2010 review probably overestimated the bleeding risk at delivery, while a relevant risk of neonatal alloimmune thrombocytopenia remains [30]. The same review reports, for the monoallelic form, 34 deliveries in 20 women and, further on, 39 completed pregnancies, an internal discrepancy that the text does not clarify [30]. In the European study of 339 pregnancies in 181 women with 13 inherited thrombocytopenias, including BSS, the count and bleeding did not worsen during pregnancy; 7 of 156 affected newborns had delivery-related bleeding and 2 died of cerebral haemorrhage [59].

3.7. Syndromic forms

BSS is part of syndromic presentations in three described situations. In the 22q11.2 deletion with a GP1BB variant on the other allele, the cardiac, immune and developmental phenotype of the deletion is added to BSS; the 15-month-old Japanese girl published in 2024 had giant platelets and thrombocytopenia without bleeding [45]. Homozygous deletion of GP1BB and SEPT5 combined severe BSS, polymicrogyria, developmental delay and a platelet secretion defect [48]. In 2026 a PEX6-associated Heimler syndrome type 2 presenting as BSS was published (letter with no abstract available) [60].

3.8. Natural history and treated disease

Most quantitative data come from treated patients, and there is no untreated natural history cohort. The overall prognosis is good with supportive care, and the risk is concentrated in provoked bleeding and delivery [1, 15, 50]. The absence of deaths in the 12 Indian patients does not equate to a zero lifetime risk: deaths from bleeding have been described in siblings of patients (two siblings of the Mauritanian case) and neonatal deaths from cerebral haemorrhage or alloimmune thrombocytopenia [41, 51, 56, 59].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

BSS should be considered in the presence of persistent chronic thrombocytopenia, a family history of thrombocytopenia, lack of response to ITP treatment, macrothrombocytopenia or absent agglutination with ristocetin [3, 21]. The Italian series add a temporal criterion: consider BSS in any macrothrombocytopenia in which it cannot be excluded that the count has been low since birth [23, 35]. A very low automated count with an uncalculated MPV or with platelets counted as lymphocytes should prompt a manual count and examination of the blood film [1, 16]. In patients with a 22q11.2 deletion, macrothrombocytopenia warrants investigation for BSS [15, 45]. Mucocutaneous bleeding with giant platelets in children of consanguineous couples suggests the biallelic form [1, 20]. The 2018 British review recommends including BSS and Glanzmann thrombasthenia in the differential diagnosis of any child with mucocutaneous or severe bleeding, especially with a family history and normal initial coagulation screening, and considering them in the investigation of suspected child abuse: in that context, in which most children are infants and aggregometry requires large blood volumes and has no reference values below 12 months, second-line investigation of purpura or bruising should include the PFA or direct analysis of platelet glycoproteins [30]. In children, biallelic BSS usually presents with unexplained purpura or bruising, gum bleeding or excessive bleeding after surgery or invasive dental treatment; gastrointestinal bleeding and haematuria occur in some patients, and haemarthrosis and spontaneous intracranial haemorrhage are unusual [30].

4.2. Warning signs of misdiagnosis

The most frequent error is a diagnosis of ITP. In Japan, re-evaluation of MPV in 112 patients diagnosed with ITP identified 11 with probable inherited macrothrombocytopenia (MPV 19.2 ± 3.8 fL; normal 7.8–10.2 fL), with 3 BSS and 1 MYH9-RD confirmed; all had received high-dose corticosteroids, splenectomy or both [61]. In the Pavia series, 4 of 13 biallelic patients had received immunoglobulin, corticosteroids or splenectomy without benefit [35], and a 2026 Pakistani report describes a young woman splenectomised for presumed ITP with only transient improvement [62]. The 2018 British review identifies three signs that should lead to consideration of BSS before splenectomy or third-line ITP therapies: a family history of “ITP”, lack of response to corticosteroids or immunoglobulin and bleeding symptoms disproportionate to the count [30]. Of four unrelated German patients with the GP9 Asn45Ser variant (NM_000174.5:p.(Asn61Ser)), three had been diagnosed with ITP [19]. The two diseases may coexist: an 8-year-old Kuwaiti girl with a GP1BB variant also had ITP treated with immunoglobulin and corticosteroids [63].

Late-onset BSS, without GP1BA, GP1BB or GP9 variants, or with two platelet populations on flow cytometry, should suggest acquired BSS: autoimmune, lymphoproliferative or myeloid [64].

4.3. Emergency signs

Emergencies include bleeding that does not stop with local measures, gastrointestinal or intracranial bleeding, head injury, menorrhagia with haemodynamic instability and postpartum haemorrhage, including delayed haemorrhage [1, 35, 57]. In a patient with repeated transfusions, failure of the count to rise after HLA-matched platelets indicates refractoriness and requires an immediate haemostatic alternative [55, 65]. In the newborn of a mother with BSS, bleeding or severe thrombocytopenia raise the possibility of alloimmune thrombocytopenia due to maternal anti-GPIb-IX or anti-HLA antibodies [56, 65].

4.4. Newborn screening

The sources consulted do not describe newborn screening programmes for BSS or for other inherited macrothrombocytopenias; diagnosis in the newborn results from targeted assessment in the event of bleeding, thrombocytopenia or a family history, and, in the children of couples with a known familial variant, from targeted genetic testing [1, 4].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal consensus-validated diagnostic criteria for BSS. The 2006 Orphanet review considers the diagnosis firm when prolonged bleeding time, macrothrombocytopenia, defective ristocetin agglutination and low or absent GPIb-IX-V expression on flow cytometry are all present [1]. For the biallelic form, the 2025 review considers that the triad of giant platelets on the blood film, absent ristocetin agglutination on light transmission aggregometry (LTA) and complete loss of GPIb-IX on flow cytometry identifies the disease, with genetic testing required to name the gene, counsel the family and identify carriers [3, 21]. The 2011 editorial proposes confirming the diagnosis by absent ristocetin agglutination, by absence or near-absence of the complex, or by both [31]. In the monoallelic form, the platelets are large but not giant, ristocetin agglutination is reduced or normal and the complex is partially reduced or normal, so phenotypic tests do not discriminate and genetic diagnosis is recommended [15, 21].

5.2. ISTH algorithm and German guideline

The 2015 guidance of the ISTH Scientific and Standardization Committee (SSC) for inherited platelet function disorders, based on expert consensus, organises the investigation in three steps [25]:

The same guidance does not recommend the PFA-100 or the bleeding time, because of insufficient sensitivity, specificity and reproducibility, which differs from the 2006 review, which included the bleeding time among the criteria [1, 25]. ISTH Table 1 lists as causes of large platelets BSS, grey platelet syndrome, the Glanzmann thrombasthenia variant, platelet-type von Willebrand disease, P2Y12 defect, δ-granule deficiency, familial predisposition to myeloid neoplasia, ARC syndrome and white platelet syndrome; as causes of abnormal ristocetin agglutination, platelet-type von Willebrand disease, BSS and GATA1 variants; and, as causes of defective GPIb/IX expression, BSS and velocardiofacial syndrome [25]. The 2025 update of the S2k guideline of the Society of Thrombosis and Haemostasis Research (GTH), an expert consensus without systematic literature review, covers children and adults and has 42 recommendations; it proposes making the diagnosis close to the patient's home, limited to the essential steps, with blood or DNA sent to specialised laboratories [66]. The algorithm starts from the personal and family history, first excludes plasma coagulopathies and, before specialised tests, immune thrombocytopenia, thrombotic thrombocytopenic purpura, haemolytic uraemic syndrome and pseudothrombocytopenia [66]. The strongest recommendations are summarised in the following table [66]:

The recommended agonists and final concentrations for LTA are ADP 2.0–3.0 µM, collagen 2 µg/mL (5 µg/mL if necessary), adrenaline 5.0 µM (10 µM if necessary), arachidonic acid 1.0–1.5 mM, thrombin receptor-activating peptide (TRAP) 10 µM and ristocetin at low dose (0.5–0.6 mg/mL, for type 2B and platelet-type von Willebrand disease) and at standard dose (1.2–1.5 mg/mL); the ristocetin concentrations of the BSS series (1.5 and 3 mg/mL, section 5.4) are therefore not interchangeable with those of all laboratories [23, 35, 66]. A 2026 review describes about 60 entities and 75 genes in congenital functional platelet disorders and proposes stepwise algorithms following the same logic [67].

5.3. Platelet count and size

Automated counters underestimate the count and MPV in macrothrombocytopenias, because they do not recognise giant platelets or count them as lymphocytes [1, 61]. In the Bolzano series, comparison of three methods in 23 patients showed that the impedance counter overestimated the thrombocytopenia relative to the optical counter and to manual counting in a Neubauer chamber (p < 0.001 for both), and 2 and 3 of these patients had, by the optical and manual methods respectively, counts at the lower limit of normal; the impedance counter did not calculate the MPV in most patients because of abnormalities of the distribution curve [23]. Phase-contrast microscopy counting in a chamber is the most reliable method in giant macrothrombocytopenias [4]. Most patients with biallelic BSS have counts between 20 and 100 × 10⁹/L, ranging from <10 × 10⁹/L to normal values and fluctuating in the same individual over time [30]. The optical counter (PLT-O) and manual counting are more accurate than impedance; fluorescence counting (PLT-F, Sysmex) stains intraplatelet mitochondria and messenger RNA, which are absent from red cells, and has been proposed to quantify macrothrombocytopenias more accurately [30].

Blood film morphometry separates inherited macrothrombocytopenias from ITP. In a Pavia study with 35 inherited macrothrombocytopenias (15 MYH9-RD, 3 biallelic BSS, 17 monoallelic BSS) and 56 ITP, with measurement within 2 hours of collection, the thresholds were as follows [68]:

In the GeneReviews chapter on MYH9-RD, a mean diameter above 3.7 µm and/or more than 40% of platelets with a diameter above 3.9 µm (about half a red cell) distinguish MYH9-RD from ITP, with a sensitivity of 86% and specificity of 87% for the first criterion and of 85% and 87% for the second [4]. These thresholds were obtained in populations with MYH9-RD and BSS in defined proportions and are not interchangeable.

5.4. Aggregometry and ristocetin agglutination

In biallelic BSS, ristocetin agglutination is absent or markedly reduced and is not corrected by the addition of normal plasma, because the receptor and not the ligand is missing, unlike in von Willebrand disease [1, 16]. Aggregation with ADP and collagen is normal, and the response to thrombin may be reduced [1, 31]. PFA closure times are markedly prolonged with the ADP and adrenaline cartridges, and the bleeding time is prolonged [30]. In many patients the count is so low that light transmission aggregometry (LTA) becomes unreliable, sometimes already below 120 × 10⁹/L; the 2006 UK Haemophilia Centre Doctors' Organisation (UKHCDO) guidelines, cited in the 2018 British review, propose adjusting the count of the control sample to that of the patient or using washed platelets with matched counts [30]. In the Pavia series, agglutination with ristocetin at 3 mg/mL was absent or markedly reduced in all 13 biallelic patients [35]. In the monoallelic Bolzano form, with ristocetin at 1.5 mg/mL, agglutination was reduced in 5 of 23 patients (mean increase in light transmission 22 ± 11.4%) and normal in 18 (82 ± 13.6%; normal 50–100%), and the 5 patients with a reduced response responded normally at 3 mg/mL [23]. In the Danish cohort, impedance aggregometry (Multiplate) with ristocetin gave reduced values in several carriers of the Copenhagen variant (15–75 U; reference 65–116 U) [24]. Normal aggregometry does not exclude monoallelic BSS [3, 21].

5.5. Flow cytometry and other protein tests

Flow cytometry quantifies CD42b (GPIbα), CD42a (GPIX), CD42c and CD42d with monoclonal antibodies; in biallelic BSS expression is low or absent [1, 25]. In the Pavia series, GPIbα was always below 10% of control; GPIX was almost undetectable with GP9 or GP1BB variants and reduced to 18–23% with GP1BA variants; GPV ranged from 5% to 33% [35]. Flow cytometry does not identify the affected subunit or gene, and it is insensitive to low amounts of antigen, so Western blotting (SDS-PAGE and immunoblotting) remains useful [1, 16, 35]. Compared with LTA, flow cytometry is less sensitive to pre-analytical variables, works with very low counts and requires a smaller blood volume, which makes it suitable in the newborn, infant and young child [30]. In the monoallelic form, flow cytometry gave the most suggestive results in the Bolzano series, with a significant reduction of all components of the complex [23]. Immunofluorescence on blood films was evaluated in an ISTH interlaboratory exercise (13 antibodies, 7 laboratories): all laboratories correctly diagnosed MYH9-RD, BSS, Glanzmann thrombasthenia and GFI1B-related thrombocytopenia [69]. Historically, the absence of GPIb was demonstrated in 1983 by a whole-blood assay with monoclonal antibodies, the forerunner of current flow cytometry [8]. Measurement of VWF and factor VIII, prothrombin time, activated partial thromboplastin time and fibrinogen exclude von Willebrand disease and coagulopathies; in BSS they are normal [1, 16, 41].

5.6. Genetic testing

Genetic testing may be Sanger sequencing of GP1BA, GP1BB and GP9, which is feasible because these genes have their coding sequence in a single exon [1, 42], or a multigene panel for thrombocytopenias and platelet disorders, or exome or genome sequencing [4]. The Padua experience shows the limits of restricted testing: in 269 patients from 140 families with suspected inherited platelet disorder, Sanger sequencing identified a pathogenic or likely pathogenic variant in 80 patients from 44 families (about 30%), BSS being the most frequent diagnosis; 70% remained without a cause, and the authors recommend an extended NGS panel [70]. Without an a priori suspected cause or inherited thrombocytopenia, the yield of panels is much lower [71]. In a retrospective paediatric series from Ankara (93 children with suspected inherited platelet disorder, August 2019 to March 2025, 14-gene panel, consanguinity in 25.8%), variants were found in 30 patients (32.3%), but 64.9% of the 37 variants were VUS and only 8.1% pathogenic; GP1BA was, together with ADAMTS13, the second most affected gene (16.2% of variants) [72]. Two patients with macrothrombocytopenia and an isolated heterozygous GP1BA variant were interpreted as monoallelic BSS; a third, with a likely pathogenic heterozygous GP1BA variant, had a maximum MPV of 11 fL, no large or giant platelets on the blood film and normal CD42a and CD42b expression, which shows that the variant, without a concordant phenotype and without segregation, is not sufficient for the diagnosis [72]. Among the children investigated for ITP, variants were found in 35.7% of refractory and 20% of chronic cases, mostly VUS [72].

Technical limits determine what a negative result means. Sequencing does not detect the 22q11.2 deletion of the missing allele, so an apparently homozygous GP1BB variant or a result suggestive of hemizygosity requires testing for the deletion by fluorescence in situ hybridisation (FISH), multiplex ligation-dependent probe amplification (MLPA) or chromosomal microarray; in the Japanese girl of 2024, the deletion was confirmed by FISH and the GP1BB variant by panel [22, 45]. Homozygous deletions encompassing GP1BB and contiguous genes, such as SEPT5, also require copy-number methods [48]. A variant of uncertain significance (VUS) neither establishes nor excludes the diagnosis; family segregation and expression studies help to reclassify it [4, 35]. ClinGen has an expert panel that has already classified variants in these genes (for example, GP9 NM_000174.5:c.182A>G and GP1BB NM_000407.5:c.236_244del) [32]. A negative result for GP1BA, GP1BB and GP9 in a late-onset BSS phenotype should lead to consideration of acquired causes and myeloid predisposition genes, such as GATA2 [64], and, with stomatocytes or haemolytic anaemia, ABCG5 and ABCG8 [73].

The report should state the gene, the transcript with version (NM_000173.7, NM_000407.5 or NM_000174.5), the HGVS notation at DNA and protein level, the zygosity (homozygosity, compound heterozygosity, hemizygosity due to deletion), the ACMG/AMP class (American College of Medical Genetics and Genomics/Association for Molecular Pathology) and, where applicable, the historical designation of the variant in mature protein numbering [17, 32].

5.7. Prenatal and preimplantation diagnosis

With the familial variants identified, prenatal diagnosis and preimplantation genetic testing are technically possible; questions of indication and counselling are addressed in section 8 [1, 4].

6. Differential Diagnosis

6.1. Principle of discrimination

The differential diagnosis of BSS is made along three axes: platelet size (small, normal, large or giant), platelet function (especially the response to ristocetin and correction by normal plasma) and extra-haematological findings, which distinguish the syndromic forms [1, 4, 25]. Small platelets point to Wiskott–Aldrich syndrome and X-linked thrombocytopenia; giant platelets with neutrophil inclusions point to MYH9-RD; heterozygous BSS, the 22q11.2 deletion, grey platelet syndrome, Montreal syndrome and Paris–Trousseau thrombocytopenia complete the group of classic macrothrombocytopenias, and aggregometry is required to separate them [1, 16]. All congenital macrothrombocytopenias are very rare [4].

6.2. Comparative table of the class

Sources of the table: [3, 4, 8, 9, 11, 12, 16, 22, 25, 38, 39, 45, 51, 60, 64, 68, 73, 77–98]. Table 4 of GeneReviews, updated in 2021, does not include TPM4, TRPM7 or TUBA8, which Orphanet already lists [4, 38].

6.3. Immune thrombocytopenia

ITP is the differential diagnosis that most often leads to inappropriate treatment. In inherited macrothrombocytopenias, the platelets are larger: in a Pavia study, a mean diameter above 3.3 µm combined with an MPV above 12.4 fL separated the inherited forms from ITP with a sensitivity of 0.97 and specificity of 0.89 [68]. In the Italian MYH9-RD registry, about 60% of index cases had a previous diagnosis of ITP and 30% received inappropriate treatments, including splenectomy [4]; in BSS, the equivalent figures are 4 of 13 biallelic patients from Pavia, 13 of 103 Bolzano patients (5 treated) and 4 of 14 Danish probands [23, 24, 35]. The distinction matters because ITP treatment does not work in BSS [3, 21]. The coexistence of ITP and BSS, described in a child with a GP1BB variant, requires assessment of the response to immunoglobulin and corticosteroids at each episode [63].

6.4. MYH9-RD

MYH9-RD (autosomal dominant; OMIM 155100) has platelet macrocytosis in 100% of patients from birth, thrombocytopenia in 98% and a bleeding tendency in 80–90% (about 30% with spontaneous bleeding). It is associated with sensorineural deafness in 80–85% (mean onset at 31 years), abnormal liver enzymes in 50%, nephropathy in 25% (mean onset at 27 years; annual progression to end-stage chronic kidney disease of 6.79 per 100 patients) and cataracts in 20% (mean onset at 37 years) [4]. Variants in the head domain cause more severe thrombocytopenia; those at residue Arg702 are associated with platelets generally below 50 × 10⁹/L, nephropathy and severe deafness before 40 years [4]. Döhle-like neutrophil inclusions appear in 42–84% on stained films and may be missed, but immunofluorescence for MYH9 aggregates has sensitivity and specificity close to 100% [4]. Platelet function is usually normal, and ristocetin agglutination is not absent, which separates it from biallelic BSS [1, 4]. The former designations May–Hegglin, Sebastian, Fechtner and Epstein now correspond to MYH9-RD [4]; OMIM adopts the designation “macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss” (MATINS), following the 2003 proposal to treat them as a single disease with a continuous clinical spectrum, because expression also varies within families with the same variant, and records that all patients have leucocyte inclusion bodies of variable size [85]. The prevalence in Italy is at least 3.75 per 1 000 000, based on a registry of 225 patients [4].

6.5. Platelet-type and type 2B von Willebrand disease

Platelet-type von Willebrand disease, allelic with BSS, and type 2B have the same routine laboratory picture, with loss of high-molecular-weight multimers and thrombocytopenia, and have been described as “non-identical twins” [3]. Mixing studies and sequencing of GP1BA and VWF separate them, and the investigation follows the 2021 ASH/ISTH/NHF/WFH guideline [3, 25]. The distinction has therapeutic consequences: the platelet type is treated with platelet transfusion, whereas type 2B is treated with VWF/factor VIII concentrate, and giving VWF in the platelet type supplies more ligand to a receptor that already binds it excessively [3].

6.6. 22q11.2 deletion

The 22q11.2 deletion reduces expression of the GPIb-IX-V complex to about 50% and is associated with mild thrombocytopenia and an increased risk of autoimmune cytopenias, including ITP [22, 35, 46]. The bleeding phenotype is generally mild, but there are more transfusions after major surgery, and specific perioperative recommendations are lacking [46]. GeneReviews recommends assessment by a haematologist if there is increased bruising or bleeding and suggests considering assessment of platelet volume and function before surgical procedures [22]. Macrothrombocytopenia in these patients should lead to GP1BB sequencing [45]. In the 2018 British review, about 90% of patients with a 22q11.2 deletion are heterozygous for BSS, because the deletion usually includes GP1BB; moderate macrothrombocytopenia is frequent, but is rarely accompanied by bleeding or abnormal ristocetin agglutination, although in one study 70% of patients had abnormal PFA closure times [30]. ITP is about 200 times more frequent, and the risk increases with the age-related decline in T lymphocytes [30]. The coexistence of MYH9-related disease in a patient with a 22q11.2 deletion and biallelic BSS due to a 22q11.2 deletion on one allele and a microdeletion affecting GP1BB on the other have been described [30].

6.7. Acquired BSS and sitosterolaemia

Acquired BSS mimics the biallelic form, with thrombocytopenia, large platelets without functional GPIb-IX and a reduced response to ristocetin; autoimmune and lymphoproliferative causes, myelodysplastic syndrome and Gaucher disease have been described, due to anti-GPIb-IX autoantibodies or to a defect of megakaryocytic origin [64]. The first acquired case, published in 1985 in a patient with lymphoproliferative disease, had an IgG antibody that inhibited the agglutination of normal platelets by ristocetin and VWF and that bound a 210 kDa antigen present on normal platelets and absent from BSS platelets [8]. In the 2025 Argentinian case, a 12-year-old girl with severe bleeding, platelets 60 × 10⁹/L, haemoglobin 6.2 g/dL and mean corpuscular volume (MCV) 105 fL had 34–37% of platelets lacking GPIb-IX on flow cytometry and a negative virtual panel of GP1BA, GP1BB and GP9 on exome sequencing; six months later leucocytosis and dysplasia appeared, and reanalysis revealed a 22 bp deletion in GATA2 (probably germline de novo, allele fraction about 50%) and variants in CSF3R, SETBP1 and ASXL1, with progression to atypical chronic myeloid leukaemia. The patient's plasma did not inhibit agglutination of normal platelets, and her megakaryocytes produced fewer CD61+CD42+ platelets, with reduced GP1BB transcript; she died at 14 years of pulmonary haemorrhage after severe COVID-19 and aspergillosis [64].

Sitosterolaemia may be mistaken for variant BSS: in Seville, a patient with macrothrombocytopenia, a moderate primary haemostasis defect and abnormal aggregation diagnosed as variant BSS had, on exome sequencing, the ABCG8 variants NM_022437.3:c.1608G>A p.(Trp536Ter) (pathogenic) and c.1394T>G p.(Leu465Arg) (likely pathogenic) [73]. Haematological abnormalities (stomatocytes, thrombocytopenia, giant platelets) are invariable in sitosterolaemia and sometimes the only initial manifestation, and the disease has its own treatment (low-phytosterol diet, ezetimibe, resins) [77].

6.8. Glanzmann thrombasthenia

Glanzmann thrombasthenia and BSS are the two severe glycoprotein platelet disorders, with pathognomonic findings and identifiable glycoprotein deficiencies [71]. In thrombasthenia, platelet count and size are normal, aggregation is absent with all physiological agonists and ristocetin agglutination is preserved; in BSS, the pattern is the reverse [1, 25]. The two share treatment with platelet transfusion, eptacog alfa (activated) and transplantation, and are addressed together in the 2018 British review [30].

7. Treatments and Risk Management Strategies

7.1. Status of recommendations

There is no BSS-specific treatment guideline, nor any randomised trial in the disease [3, 30]. The available guidance consists of expert reviews (from 2012, 2018 and 2025), observational series (the SPATA study, on surgery in inherited platelet disorders, and the European study of pregnancy in inherited thrombocytopenias), a phase II trial of eltrombopag that included two patients with monoallelic BSS, and case reports [21, 26, 28, 30, 53, 59]. The British review summarises the consensus: patients should be referred to a specialist bleeding disorders centre; they do not need routine prophylaxis; management focuses on prophylaxis before high-risk procedures, treatment of non-surgical bleeding and, in women, menorrhagia and pregnancy; and there is no uniform approach, so treatment is individualised according to the type of lesion or procedure, the extent of bleeding and the presence or absence of platelet refractoriness, and may differ between episodes in the same patient [30]. No medicine has an approved indication for BSS; all the doses below come from labels for analogous indications or from published series, and their use in BSS is off-label, except where otherwise stated [27, 99].

The monoallelic form rarely needs treatment: in the Bolzano series, none of the 103 patients had abnormal bleeding at extractions or surgery, and 32 deliveries took place without transfusion [23]. The measures in this section apply mainly to the biallelic form and to monoallelic forms with bleeding.

7.2. General measures and prevention

General measures include avoiding trauma and antiplatelet agents, in particular aspirin and non-steroidal anti-inflammatory drugs (NSAIDs); maintaining regular dental hygiene; vaccinating against hepatitis B, because of exposure to blood products (the 2018 British review recommends vaccinating all patients against hepatitis A and B); correcting iron deficiency; and starting hormonal contraception in girls from puberty [1, 26]. The European patient association recommends an individualised bleeding management plan [50]. By extrapolation from the MYH9-RD model, contact sports should be avoided when thrombocytopenia is severe [4]. Distinguishing the condition from ITP avoids corticosteroids, immunoglobulin and splenectomy, which have no benefit in BSS [21, 35].

The 2018 British review details the organisation of care: registration of all patients at a specialist bleeding disorders centre with a 24-hour service; an alert card with the diagnosis, the centre's contact details and, where present, the platelet antibodies; education of the patient and family about situations of bleeding risk, compression for epistaxis, oral hygiene and regular dental visits; avoidance of high-risk sports; avoidance of over-the-counter medicines that interfere with platelet function, informing prescribers, in a list that includes, besides aspirin and NSAIDs, some antibiotics, antihistamines and psychotropic drugs; family study and counselling on the mode of inheritance; iron supplementation for anaemia due to menorrhagia or recurrent epistaxis; and multidisciplinary follow-up with a haematologist, dentist, specialist nurse and gynaecologist, with transition from paediatric to adult services at the age and time appropriate for the patient [30].

7.3. Local haemostatic measures

Local measures are the first line for mucosal bleeding: compression with gauze soaked in tranexamic acid, fibrin sealants, dental splints after extractions and nasal packing [16, 26]. By extrapolation from MYH9-RD, epistaxis may require packing or endoscopic cauterisation, and gum bleeding may be treated with tranexamic acid mouthwash [4].

7.4. Antifibrinolytics

Tranexamic acid is used for mild to moderate mucocutaneous bleeding, minor surgery and as an adjunct to transfusion or eptacog alfa (activated) [4, 21, 26]. More than half of the patients with inherited functional platelet disorders in the American ATHN registry received antifibrinolytics [52]. In the SPATA study, surgical prophylaxis with an antifibrinolytic alone was associated with excessive bleeding in 17.6% of procedures (odds ratio, OR, 0.31 relative to no treatment) [53]. There is no defined dose for BSS; the doses published in reports and those on the labels are as follows:

Renal adjustment (Portuguese label of the solution for injection, serum creatinine): 120–249 µmol/L (1.35–2.82 mg/dL), 10 mg/kg every 12 h; 250–500 µmol/L, 10 mg/kg every 24 h; >500 µmol/L, 5 mg/kg every 24 h [100]; the US label uses equivalent thresholds and doses (10 mg/kg twice daily, once daily, or every 48 h or 5 mg/kg every 24 h) [101]. Contraindications include neuraxial administration (intrathecal or epidural), subarachnoid haemorrhage, active intravascular coagulation and hypersensitivity [101]; the Portuguese label adds severe renal impairment and a history of seizures, and reports seizures associated with treatment [100]. The adverse effects described include allergic or anaphylactic reactions and headache [53]. Undiluted intravenous infusion should be slow, at no more than 1 mL/min, to avoid hypotension [101]. In Portugal several brands of tranexamic acid are authorised (for example, Tafixyl®, Ataxanic®, Medsamic®) and in Brazil Transamin® and other brands and generics with active ANVISA registration [100, 102]. The GeneReviews entry on MYH9-RD also includes ε-aminocaproic acid among the antifibrinolytics, without a dose for these diseases [4].

7.5. Hormonal treatment of menorrhagia

Menorrhagia is the main cause of anaemia and severe bleeding in women with biallelic BSS [35, 41]. The 2018 British review defines heavy menstrual bleeding as a duration of more than 7 days and/or a loss of more than 80 mL per cycle, notes that it may be the presenting symptom and cites an Indian series of 130 women with rare bleeding disorders, followed for 15 years, in which 44 of the 50 of post-menarchal age had menorrhagia (17 with Glanzmann thrombasthenia and 2 with BSS) [30]. The same review proposes a therapeutic sequence: first, weight-adjusted tranexamic acid during the period; if insufficient and pregnancy is not desired, a progestogen alone or an oestrogen–progestogen; for bleeding that requires it, high-dose norethisterone (5–10 mg every 6 to 8 h) at least in the initial phase of the cycle, reduced according to symptoms and with withdrawal bleeding expected on stopping, followed by maintenance with a combined oral contraceptive; the levonorgestrel intrauterine device (Mirena®), whose insertion may require haemostatic support as for minor surgery; and, for refractory or life-threatening menorrhagia, uterine artery embolisation, endometrial ablation or hysterectomy, usually reserved for women who have completed their families [30]. Intravenous conjugated oestrogens for 1–2 days in acute bleeding were proposed in one report but are not current practice; cultural or religious objections to hormonal therapy may limit treatment [30]. High-dose intranasal desmopressin was evaluated in menorrhagia in severe platelet disorders and was ineffective [30]. The 2012 review proposes: for bleeding at menarche, high-dose oestrogen followed by high-dose oral oestrogen–progestogen; for later menorrhagia, combined oral contraceptives in a continuous regimen; and, when oestrogen–progestogens are contraindicated, depot medroxyprogesterone acetate every 3 months [26]. The review gives no numerical doses. The Portuguese label of Depo-Provera® 150 mg/mL (medroxyprogesterone acetate) indicates, for contraception, 150 mg by intramuscular injection every 12 weeks, with a maximum tolerance of 5 days after the scheduled date, warns of loss of bone mineral density with prolonged use in women of all ages, and is not indicated before menarche [103]. The thrombotic risk of oestrogens should be weighed [4]. Oral tranexamic acid is the non-hormonal alternative (7.4).

7.6. Desmopressin

Desmopressin (1-deamino-8-D-arginine vasopressin, DDAVP) increases VWF and factor VIII and shortened the bleeding time in some patients with BSS [1, 26]. In two Swedish patients (1991), the infusion shortened the bleeding time without normalising it, and in the two siblings homozygous for GP9 Leu40Pro (NM_000174.5:p.(Leu56Pro); 1998) it normalised it; these are isolated observations of a laboratory marker, without bleeding outcomes [8, 19]. Efficacy in BSS has not been studied in a controlled way: a 2025 review considers it of limited use, with modest benefit as an adjunct in selected procedures [54], and in SPATA desmopressin was associated with excessive bleeding in 8.1% of procedures in functional platelet disorders (OR 0.13; 95% CI 0.04–0.45) and the combination with an antifibrinolytic in 8.3% (OR 0.13), without stratification for BSS in the text read [53].

The 2018 British review assigns desmopressin a limited role in platelet glycoprotein deficiencies: the increase in factor VIII, VWF and platelet adhesiveness could be advantageous in theory, but the results in BSS are equivocal [30]. In SPATA, according to the same review, most procedures in patients with biallelic BSS were covered with desmopressin alone (15) or combined with an antifibrinolytic (23) (see 7.17) [30].

Sources: [104, 105]. The regulatory difference is relevant: in Portugal, congenital platelet dysfunction with prolonged bleeding time is part of the approved indication, whereas in the USA use in BSS is off-label [104, 105]. The US label does not cover platelet-type von Willebrand disease [3]. In Brazil, DDAVP® (Ferring) has active ANVISA registration; the Brazilian package leaflet was not consulted [102]. The adverse effects described are headache, nausea, hypotension and, at times, hyponatraemia and renal dysfunction [53].

7.7. Platelet transfusion

Platelet transfusion is the main treatment for severe bleeding and for prophylaxis of high-risk surgery [1, 21]. It should be selective and sparing, because it exposes the patient to alloimmunisation against HLA antigens and, specifically in BSS, against the GPIb-IX-V complex that the patient has never expressed, with refractoriness to subsequent transfusions [16, 26, 65]. The use of HLA-matched single-donor platelets is recommended and, failing that, leucodepleted components [26]. By extrapolation from MYH9-RD, transfusion is reserved for bleeding that cannot be controlled by other means, that threatens life or an organ or is at critical sites, and for prophylaxis of surgery or delivery [4]. In SPATA, 97.1% of the platelets transfused came from fresh random donors (34.2% HLA-matched) and 2.9% were cryopreserved, and biallelic BSS received preoperative prophylaxis in 97.2% of procedures [53]. In a Dutch survey of haematologists (20 responses; 36 patients with thrombasthenia and 29 with BSS under follow-up), 75% gave HLA-matched platelets pre-emptively in the elective setting, with the aim of preventing alloimmunisation and preserving the efficacy of random platelets in emergencies; anti-HLA antibodies were recorded in 5 patients with BSS [106]. The review cited in the Indian study states that, according to British guidelines, unselected platelets are reserved for severe life-threatening bleeding and eptacog alfa (activated) is preferred for severe non-life-threatening bleeding (indirect attribution) [51]. The sources consulted do not define a dose or count threshold specific to BSS; in the 2026 Iranian case, the pregnant woman received single-donor apheresis platelets, leucoreduced, irradiated and crossmatched [36].

The 2018 British review directly cites the 2006 UKHCDO and the 2016 British Society for Haematology (BSH) guidelines on platelet transfusion: local measures and antifibrinolytics for less severe bleeding; eptacog alfa (activated) preferred to transfusion for non-life-threatening bleeding in which the bleeding site can be assessed; unselected platelets only for life-threatening bleeding in which delay would be dangerous; and platelet transfusion as first line in major surgery and severe bleeding when local measures and antifibrinolytics have failed [30]. Platelets should preferably be leucodepleted and HLA-matched, which may not be feasible in an unplanned situation [30]. To the risks of any blood product (allergic reactions, volume overload, transfusion-related acute lung injury) is added the higher risk of transfusion-transmitted bacterial infection, because platelets are stored at 20–24 °C: about 1 in 12,000 units of whole blood-derived platelets and 1 in 60,000 apheresis units, according to 2005 estimates that a later American study suggests are underestimates [30].

7.8. Alloimmunisation and refractoriness

Anti-HLA and anti-GPIb-IX antibodies may make future transfusions ineffective, and anti-GPIb-IX antibodies cross the placenta and may cause fetal or neonatal thrombocytopenia and bleeding [65]. The 2018 review recommends monitoring platelet antibodies after each transfusion and, in women, during and after pregnancy, and reports safety and efficacy data for eptacog alfa (activated) in patients with antibodies [65]. In the 2026 Japanese case, more than 200 units of platelets over 10 years led to anti-HLA antibodies and haemostatic failure of standard and HLA-matched platelets [55]. Transfusions of red cell concentrate without phenotyping also cause alloimmunisation: the Mauritanian patient developed anti-E, anti-c and anti-Fya, with two transfusion reactions, and came to require phenotyped blood [41]. For pregnancy, intravenous immunoglobulin, plasmapheresis and corticosteroids have been reported to improve the response to platelets and prevent neonatal alloimmune thrombocytopenia [58].

The 2018 British review quantifies the problem mainly on the basis of Glanzmann thrombasthenia: historical series describe alloantibodies in 25–70% of patients; after universal leucodepletion of cellular components in the United Kingdom (1999), HLA alloimmunisation fell, but may still reach 10–25%; in the international thrombasthenia registry, 65 of 218 treated patients (30%) developed platelet antibodies (47 anti-GPIIb/IIIa and 21 anti-HLA) [30]. In BSS, the risk has been less studied and is probably lower than in thrombasthenia [30]. The review proposes a serological surveillance protocol: HLA typing and baseline anti-HLA antibody screening at diagnosis; testing for platelet glycoprotein-specific antibodies if there were transfusions before diagnosis; anti-HLA and anti-glycoprotein antibody testing 2–3 months after the last transfusion, before any surgery or procedure in which platelets are expected to be needed and at the first antenatal visit; and, as good practice, annual repetition [30]. In already alloimmunised patients with severe bleeding, it recommends high doses of platelets combined with eptacog alfa (activated), and mentions antibody removal by plasmapheresis or immunoadsorption, described in thrombasthenia [30].

7.9. Eptacog alfa (activated), recombinant activated factor VII

Eptacog alfa (activated) (rFVIIa; NovoSeven®) is recommended in the reviews for alloimmunised patients or those with transfusion failure [21, 65]. The 2018 British review stresses that it is not licensed for BSS, but was used successfully in paediatric series and in severe bleeding in patients with BSS (2003 and 2005) and is an alternative to platelets, especially for procedures in refractory patients [30]. The doses in that review derive from the accumulated experience in Glanzmann thrombasthenia [30]. In BSS it is always off-label: the US and EU labels include Glanzmann thrombasthenia but not BSS [27, 99]. The doses used in BSS derive from the Glanzmann thrombasthenia label and from case reports:

The table of published cases compiled in 2026 also describes a 39-year-old woman with recurrent gastrointestinal bleeding (dose not stated, 5 days), two sisters aged 15 and 24 years with severe epistaxis and menorrhagia (about 90–122 µg/kg, 2–3 boluses per episode), two relatives aged 28 and 30 years with gastrointestinal bleeding, menorrhagia and dental extraction (90 µg/kg before and during the procedure, repeated every 2–3 h), two siblings with knee and eye surgery, dental extraction and gastrointestinal bleeding (90 µg/kg every 3 to 4 h perioperatively) and a 17-year-old girl (1 mg, about 15 µg/kg, every 2 to 3 h intraoperatively), all with haemostasis and without thrombosis [55]. In SPATA, prophylaxis with eptacog alfa was associated with excessive bleeding in 18.5% of procedures (OR 0.33; 95% CI 0.11–0.95), without stratification for BSS [53].

The US label carries a boxed warning for serious arterial and venous thrombotic events, advises against concurrent use with activated prothrombin complex concentrate and states that coagulation parameters do not correlate with efficacy [27]; the EU SmPC recommends caution in patients with thromboembolic risk factors [99]. The authors of the Japanese case stress that the review of BSS cases shows no major thrombotic events, but the number is small, the cost is high and there is no standardised dose; they propose early initiation of eptacog alfa when there is refractoriness and major bleeding or surgery, with a concomitant antifibrinolytic, and call for dose consensus and registries [55]. The Kuwaiti authors state that efficacy has been demonstrated in randomised trials, but do not identify them, and no randomised trial in BSS was found in the sources consulted [54, 107]. In Portugal, NovoSeven® has a centralised EU marketing authorisation, with presentations of 50, 100 and 250 KIU in Infomed; in Brazil, NovoSeven® (alfaeptacogue ativado) has active ANVISA registration, valid until May 2027 [99, 102]. In Japan, eptacog alfa became available in Glanzmann thrombasthenia regardless of the presence of alloantibodies or refractoriness, and a 2026 Japanese review proposes considering it in patients at risk of alloimmunisation [108].

7.10. Thrombopoietin receptor agonists

Eltrombopag (Revolade® in the EU and Brazil, Promacta® in the USA), an oral thrombopoietin receptor agonist, was studied in inherited thrombocytopenias in an open-label, dose-escalation phase II trial at 5 Italian centres (April 2015 to May 2017; NCT02422394), with 24 patients: 9 with MYH9-RD, 9 with ANKRD26-related thrombocytopenia, 3 with Wiskott–Aldrich syndrome or X-linked thrombocytopenia, 2 with monoallelic BSS due to the Bolzano variant and 1 with ITGB3-related thrombocytopenia [28, 107]. In part 1, patients received 50 mg/day for 3 weeks and, if the count on day 21 was ≤100 × 10⁹/L, 75 mg/day for a further 3 weeks. Twenty-one of 23 evaluable patients responded (91.3%; 95% CI 72.0–98.9): 11 with a major response (>100 × 10⁹/L) and 10 with a minor response (at least double the baseline value); the mean increase was 64.5 × 10⁹/L (95% CI 43.7–85.3), and 10 of the 12 patients with spontaneous bleeding at baseline had complete remission. The two patients with monoallelic BSS had a major response with 50 mg/day. There were 7 adverse events in 5 patients, all grade 1 (headache or transient bone pain and one rise in creatinine due to urinary retention), and 30 days after stopping, the count and the bleeding tendency returned to baseline [28]. A 2026 editorial includes monoallelic BSS among the forms that respond and proposes thrombopoietin receptor agonists as the preferred option for elective surgical preparation in many inherited thrombocytopenias, noting that failure of one agonist does not exclude a response to another [109]. In biallelic BSS, in which the adhesion defect persists at any count, the sources consulted do not describe the use of these medicines.

The trial dose coincides with the starting dose and the maximum of the ITP labels [28, 111, 112]. The 2026 Portuguese series (Porto) had a favourable response in 14 of 15 procedures, a major response in 10, a median baseline of 45 × 10⁹/L, a median increase of 143% and a median peak of 103 × 10⁹/L, without bleeding or transfusion [110]. Avatrombopag was used in 3 episodes in 3 patients with inherited thrombocytopenias other than BSS (20 to 40 mg/day), also off-label [113]. In a Kuwaiti child with a GP1BB variant and a germline ETV6 variant, eltrombopag was withdrawn because of the leukaemic risk associated with ETV6 [63]. In Brazil, Revolade® and generics of eltrombopague olamina have active ANVISA registration [102]. Patients with inherited thrombocytopenia are not protected against thrombosis, and postoperative thromboprophylaxis should not be omitted solely because of a low count [109].

7.11. Haematopoietic stem cell transplantation

Allogeneic haematopoietic stem cell transplantation (HSCT), from bone marrow or cord blood, is reserved for the rare cases with life-threatening or refractory bleeding [1, 21]. In the Pavia series, two siblings were cured by HSCT from HLA-identical related donors [35, 114]. In 2006 another report of allogeneic HSCT in severe BSS was published [115]. The German boy with homozygous deletion of GP1BB and SEPT5 received HSCT from an HLA-identical unrelated donor, became free of bleeding after engraftment and had a marked improvement in mental development [48]. The Argentinian patient with acquired BSS due to GATA2-associated myeloid neoplasia had HSCT planned at the time of her death [64]. The sources consulted do not compare the results of HSCT with those of supportive treatment. The 2018 British review recommends considering HSCT in patients with BSS with severe bleeding problems and/or platelet antibodies, and notes that gene therapy has been studied in animal models of thrombasthenia and that BSS may become a candidate [30].

7.12. Gene therapy and preclinical research

Gene therapy is at the preclinical stage. In a murine model lacking GPIbα, a lentiviral vector carrying human GP1BA under the integrin αIIb promoter, introduced into haematopoietic progenitor cells, produced therapeutic expression of human GPIbα, corrected the bleeding time and improved the macrothrombocytopenia, with the effect maintained in serial transplants and anti-human GPIbα antibodies in 1 of 17 animals [116]. In the same model, 10–20% of transduced progenitor cells were sufficient to correct the bleeding time; non-myeloablative conditioning with busulfan corrected the phenotype in 21 of 27 animals, with antibodies and immune thrombocytopenia in 8 of 27 (resolved by 30 weeks), and the addition of antithymocyte globulin prevented the antibodies and increased engraftment [117]. Lentiviral rescue of GPIbβ-deficient mice corrected the phenotype [49]. For BSS type C, a group from Granada, with co-authorship from the Coimbra Hospital and University Centre, used lentiviral vectors to correct the expression, localisation and function of GPIX in megakaryoblastic lines and in induced pluripotent stem cells lacking GP9, and the progenitor cells of two unrelated patients, once transduced, produced megakaryocytes and platelets with GPIX and of smaller size [7].

7.13. Comparative regulatory status

Sources: [27, 99–102, 104, 105, 109, 111, 112].

7.14. Trials and comparative evidence

The search of ClinicalTrials.gov in October 2026, with the terms “Bernard-Soulier”, “inherited platelet disorder” and “inherited thrombocytopenia”, found no interventional trials specific to BSS; the phase 2 trial of eptacog beta (NCT07136857), recruiting since 2 October 2025, is for Glanzmann thrombasthenia only [107]. A negative search does not exclude unregistered studies. The evidence has limits that condition its reading: the eltrombopag trial is open-label, without a control group, with two patients with BSS and with a transient response that disappears 30 days after stopping; the SPATA results are observational, subject to confounding by indication, and the odds ratios compare prophylaxis chosen by clinicians, not randomly assigned; the eptacog alfa data in BSS are case reports, subject to publication bias towards successful cases. No indirect comparisons are made between these studies.

7.15. Developments in the last 12 months

No marketing authorisation applications, regulatory opinions or trials with results specific to BSS were identified in the period.

7.16. Pregnancy, delivery and puerperium

Pregnancy in a woman with biallelic BSS should be planned and delivery should take place in a tertiary centre, with obstetrics, haematology, neonatology, anaesthesia and transfusion medicine [56, 58]. The 2010 systematic review recommends a multidisciplinary team, an individualised plan and an international registry [56], and the 2023 review concludes that the optimal mode and timing of delivery are uncertain, but that peripartum prophylaxis is associated with less postpartum haemorrhage [57]. The recommendations compiled by the 2026 review, from the 2010 review, are as follows: in uncomplicated vaginal delivery, eptacog alfa (activated) 90 µg/kg every 2 h, 3–4 doses or until haemostasis (no maximum dose defined in the source), with tranexamic acid; in caesarean section or in bleeding at vaginal delivery, HLA-matched platelets with tranexamic acid; prophylactic tranexamic acid at delivery and continued for at least 2 weeks postpartum, because of the frequency of delayed postpartum haemorrhage; uterotonics used actively in the third stage; avoidance of difficult instrumental deliveries; and postpartum surveillance up to 6 weeks [58]. Regional anaesthesia is generally contraindicated, because of the risk of spinal or epidural haematoma, and caesarean section is performed under general anaesthesia [58]. Eptacog alfa is useful in refractoriness, with assessment of thromboembolic risk, especially in caesarean section [58]. The EU SmPC of NovoSeven® includes severe postpartum haemorrhage, when uterotonics are insufficient, at a dose of 60–90 µg/kg as an intravenous bolus, with a second dose according to the response [99].

Prophylactic transfusion should be cautious, because maternal alloimmunisation against GPIb-IX or HLA may cause fetal or neonatal alloimmune thrombocytopenia and intracranial haemorrhage in the newborn; antibodies should be monitored during and after pregnancy [58, 65]. In the European study of inherited thrombocytopenias, transfusion at delivery was more frequent in women with severe bleeding before pregnancy and with platelets <50 × 10⁹/L at delivery, and the MYH9-RD model recommends a count ≥50 × 10⁹/L for delivery [4, 59]. The 2026 Iranian pregnant patient received 4 prophylactic transfusions of apheresis platelets during pregnancy, had induction with a cervical catheter and misoprostol 25 µg sublingually, tranexamic acid 1 g intravenously at induction, vaginal delivery with an active phase of less than 2 hours and postpartum haemorrhage treated with platelets, with a favourable maternal and neonatal outcome [36]. The 19-year-old Turkish pregnant patient of the 2023 review received prophylactic single-donor platelets and oral tranexamic acid and had a caesarean section for failure to progress in labour, without complications [57]. These approaches describe isolated cases and do not replace an individual plan.

The 2018 British review summarises the 2006 UKHCDO guidance for women with severe platelet disorders, including BSS: bleeding prophylaxis at delivery in all cases; in vaginal delivery, eptacog alfa (activated) 90 µg/kg immediately before delivery, with an antifibrinolytic, repeated every 2 h for a minimum of 3–4 doses; HLA-matched platelets as an alternative in vaginal delivery and as first line in caesarean section [30]. The authors accept that this guidance may have to be revised in the light of the 2014 and 2015 data, which show less bleeding than the earlier literature (see 3.6) [30]. The principles of pregnancy management proposed by the same review are as follows:

Source: [30]. The window of risk for delayed postpartum haemorrhage differs between the reviews: up to 8 weeks in the 2018 review and surveillance up to 6 weeks in the 2026 review [30, 58]. In thrombasthenia, the same review recommends monitoring alloimmunisation from confirmation of pregnancy and measuring the newborn's platelet count at birth [30].

7.17. Surgery, procedures and anaesthesia

SPATA, a worldwide retrospective study of the scientific working group of the European Hematology Association (EHA-SWG), analysed 829 procedures in 423 patients (age 2–91 years, median 40) from 49 centres in 17 countries, with 238 functional platelet disorders and 185 thrombocytopenias; biallelic BSS was classified among the former and the monoallelic form among the latter [53]. Excessive bleeding occurred in 19.7% of procedures (24.8% in functional platelet disorders and 13.4% in thrombocytopenias), and biallelic BSS had the highest frequency, 44.4%, despite having received preoperative prophylaxis in 97.2% of procedures [53]. The predictors were a WHO bleeding score ≥2 before surgery, the type of disease, cardiovascular and urological surgery and female sex; in thrombocytopenias, a count <68 × 10⁹/L and age >70 years. Prophylaxis was associated with less bleeding in functional platelet disorders, but not in thrombocytopenias [53]. The British review focuses management on prophylaxis before high-risk procedures [30]. According to that review, SPATA included 36 procedures in 17 patients with biallelic BSS; most were covered with desmopressin alone (n = 15) or combined with antifibrinolytics (n = 23), others with platelets alone (n = 9) or antifibrinolytics alone (n = 9), and none received eptacog alfa; the sum of the published categories exceeds the number of procedures and cannot be reconciled without the original table [30]. The data did not allow the authors to recommend a preoperative regimen for BSS [30]. In monoallelic BSS, thrombopoietin receptor agonists are an option for elective surgical preparation, started about 3 weeks beforehand [109, 110]. In the 22q11.2 deletion, which frequently involves cardiac surgery, it is recommended to consider assessment of platelet volume and function before surgery [22]. Indicated postoperative thromboprophylaxis should not be omitted solely because of thrombocytopenia [109].

7.18. Agents to avoid and special situations

Aspirin and other NSAIDs and antiplatelet agents should be avoided [1, 26]. By extrapolation from MYH9-RD, heparin and oral anticoagulants are used with caution, after assessment of risks and benefits, and some antidepressants, antibiotics and anaesthetics that interfere with platelet function are avoided [4]. Desmopressin is contraindicated in hyponatraemia and, according to the Portuguese SmPC, in type 2B von Willebrand disease [104, 105]. Tranexamic acid is contraindicated for neuraxial administration [101]. Eltrombopag was withdrawn in a child with a germline ETV6 variant, because of the leukaemic risk [63]. The British review addresses children and adults within the same specialist centre model and provides for transition from paediatric to adult services at the age and time appropriate for the patient, without a specific protocol [30].

7.19. Guideline recommendations and differences

Sources: [1, 21, 25–27, 30, 50, 51, 54, 58, 66, 99, 106]. When the dose in a review and that on the label differ, the review or trial dose is used, with the label as a comparison: for eptacog alfa, the BSS reports use 90 µg/kg at intervals of 2–3 h, closer to the EU SmPC than to the maximum interval of 6 h of the US label [27, 55, 99].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

8.2. Cascade testing and carriers

Once the proband's variants have been identified, testing relatives allows carriers and patients with a mild form to be identified. Obligate carriers of recessive variants are usually asymptomatic, with a normal count and platelet diameter at the upper limit of normal, but there are exceptions: in the Pavia series, carriers of GP9 p.Leu63Pro had expression of the complex of about 50% and reduced ristocetin agglutination [35]. In monoallelic BSS, testing of relatives found 61 additional carriers in the Bolzano series, all with a low count on the impedance counter, and a normal count in all relatives without the variant [23]. Flow cytometry does not replace genetic testing in the identification of carriers, because expression in carriers varies between normal values and about 50% of control [35]. In families with a 22q11.2 deletion and macrothrombocytopenia, the study should include GP1BB [45]. Germline mosaicism is not described in the sources consulted for these genes.

8.3. Prenatal diagnosis and preimplantation genetic testing

The 2006 review considered prenatal diagnosis technically feasible with the familial variant known, but “probably not justified”, because the syndrome rarely causes fatal bleeding and because cordocentesis and chorionic villus sampling carry a risk of bleeding and miscarriage [1]. The 2012 review includes prenatal diagnosis among the preventive measures for severe platelet disorders [26]. Preimplantation genetic testing is possible when the familial variants have been identified [4]. The decision depends on the severity observed in the family (for example, deaths of siblings from bleeding, as in the Mauritanian family), on the availability of treatment and on the couple's values [41, 51]. In planning the delivery of a pregnant carrier or affected woman, the fetal status and the risk of alloimmune thrombocytopenia guide the choice of mode of delivery and the neonatal preparation [58, 59].

8.4. Counselling of minors and adolescent girls

Testing a minor is justified when it changes management, as in a child with bleeding, a child due to undergo surgery or a girl before menarche [1, 26]. Carrier testing for a recessive variant in an asymptomatic child does not change management and may wait until the age at which the person can decide. The adolescent girl with biallelic BSS should receive, before menarche, information about menorrhagia, the hormonal plan and tranexamic acid [26, 35]. In the adolescent with BSS planning a pregnancy, counselling should include the risk of postpartum haemorrhage (52.9% in the 2023 review) and of neonatal alloimmune thrombocytopenia [57, 65].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Orphanet does not give a point estimate of prevalence, and the value <1/1 000 000 is the upper limit of a class [5]. The monoallelic forms are probably more frequent than the classic form and are under-ascertained, and the published rate for “BSS” describes mainly the severe recessive form [3]. In the Pavia series, the 13 biallelic patients and 4 earlier cases were the only Italian families known in 2011 [35]. In the database of 216 inherited thrombocytopenias of the Italian centres, there were 42 families with monoallelic Bolzano BSS, 22 with MYH9-RD, 21 with thrombocytopenia 2 and 10 with biallelic BSS [23].

9.2. Founder populations and regions with consanguinity

The Bolzano variant is a founder variant of southern Italy: 32 of the 42 families originated from the south, mainly Campania and Sicily, and all carriers shared the rare T-T-B haplotype; the authors accept that it may have spread with 20th-century Italian emigration, with no cases described outside Italy in 2012 [23]. The Copenhagen variant is a Danish founder variant, shared across a 2.0 Mb region by six unrelated probands [24]. The GP9 Asn45Ser variant (p.(Asn61Ser)) is recurrent in several European families from different countries, with a probable founder effect [1, 43]: it was identified in four unrelated German patients from different federal states and in British, Austrian, Swedish, Belgian and several Finnish patients, which led the authors to propose an ancient variant shared by the populations of northern and central Europe [19]. In Sweden, the patient homozygous for GP1BA Trp498Ter (NM_000173.7:p.(Trp540Ter)), studied since 1991, was the son of parents with common ancestors in the 17th century [8, 13]. The GP1BB variant described by Barozzi as the second cause of monoallelic BSS in Italy suggests heterogeneity within the same country [44]. In regions with frequent consanguinity, the biallelic form is more common: in southern Tunisia, among 60 congenital platelet disorders diagnosed from 1982 to 2024 (consanguinity 71.6%), there were 54 Glanzmann thrombasthenias, 5 BSS and 1 Wiskott–Aldrich syndrome [118]; in Senegal, among 7 confirmed patients, all children of consanguineous marriages, there was 1 BSS [119]; in Iran, novel variants were described in 8 patients [42]; and in Kuwait and Mauritania the cases published in 2025–2026 are children of consanguineous parents [41, 54]. In India, Glanzmann thrombasthenia and BSS account for about 4–5% of the bleeding disorders diagnosed in coagulation laboratories, according to the Mumbai study [51].

9.3. Portugal and Brazil

The sources consulted contain no epidemiological data on BSS in Portugal or Brazil. Portuguese research appears in the co-authorship of the Coimbra Hospital and University Centre in the work on gene therapy for BSS type C and in the Porto series on perioperative eltrombopag in inherited thrombocytopenias, which did not include patients with BSS [7, 110]. The medicines used in BSS are available in both countries (section 7.13) [99, 100, 102]. The absence of data in these sources does not demonstrate the absence of patients or of publications.

9.4. Special populations

Women are the population with the greatest burden of morbidity, because of menorrhagia and postpartum haemorrhage [35, 57]. Patients with a 22q11.2 deletion have, in addition to the risk of GP1BB-related BSS, a risk of ITP and of cardiac surgery with more transfusions [22, 46]. In resource-limited settings, HLA-matched or leucodepleted platelets are frequently unavailable, and the deaths from bleeding recorded in the Indian Glanzmann thrombasthenia cohort were attributed to lack of treatment [51]. In patients of East or Southeast Asian ancestry, the starting dose of eltrombopag on the label is 25 mg/day [111].

9.5. Reference networks and patient associations

The relevant European network is ERN EuroBloodNet, which covers rare bleeding and platelet disorders [29]. The European Haemophilia Consortium maintains a BSS factsheet for patients, and the World Federation of Hemophilia covers inherited platelet disorders [50, 120]. In Portugal there is the Associação Portuguesa de Hemofilia e de outras Coagulopatias Congénitas [121]. Orphanet maintains the ORPHA:274 page [5].

10. Illustrative Clinical Case

10.1. Biallelic BSS due to a homozygous GP1BB variant (Mauritania, 2026)

A Mauritanian girl, the daughter of first-cousin parents, had two siblings who had died of a bleeding syndrome; her two sisters and her parents were asymptomatic [41]. From 6 months of age she had epistaxis, gum bleeding and spontaneous purpura, and received repeated transfusions without a diagnosis. At 14 years, assessment showed haemoglobin 5.2 g/dL, MCV 74.3 fL, mean corpuscular haemoglobin (MCH) 14.6 pg, platelets 32 × 10⁹/L (32 000/mm³), Ivy bleeding time 10 min (normal <5), VWF ristocetin cofactor activity 75%, normal prothrombin time, activated partial thromboplastin time and fibrinogen, normal clot retraction and a negative direct antiglobulin test. The blood film showed giant platelets, some larger than red cells, single and in aggregates (Figure 1 of the paper: https://pmc.ncbi.nlm.nih.gov/articles/PMC12823461/figure/mgg370186-fig-0001/). On flow cytometry, with the antibodies SZ1 (anti-GPIX), SZ2 (anti-GPIbα) and GRP (anti-GPIb-IX), the patient's curves overlapped the isotype control, whereas AP3 (anti-GPIIIa) binding was superimposable on that of the control: absence or marked reduction of the GPIb-IX complex with normal αIIbβ3 (Figure 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC12823461/figure/mgg370186-fig-0002/) [41].

Sanger sequencing identified a homozygous GC duplication in GP1BB, described in the genomic sequence AF006988.1 as g.13373_13374dupGC (reference transcript NM_000407.4), with a frameshift from residue Ala115 (p.Ala115Profs16 in the abstract) [41]. The paper does not provide the HGVS c. notation, and the text describes 52 novel amino acids and a protein of 167 instead of 181 amino acids, which does not match the notation in the abstract; because only a genomic GenBank coordinate is given, the variant was not normalised in VariantValidator [41]. A year later, menarche worsened the anaemia and required transfusions of red cell concentrate and platelets; the patient developed anti-E, anti-c and anti-Fya alloantibodies, with two incompatibility transfusion reactions, and red cell transfusions were stopped in the absence of phenotyped blood. At 32 years she had haemoglobin 7 g/dL, chronic microcytic anaemia and only minimal gum bleeding and epistaxis; management consisted of transfusions, antifibrinolytics and avoidance of antiplatelet agents and NSAIDs [41].

The case brings together the central elements of the biallelic form: consanguinity and bleeding deaths among the siblings, mucocutaneous bleeding from the first year of life, late diagnosis, giant platelets with a selective defect of the GPIb-IX complex, chronic iron deficiency and transfusion alloimmunisation. The bleeding time, used here in the diagnosis, is not recommended by the ISTH, and the case does not describe hormonal treatment of menorrhagia or extended red cell phenotyping before the first transfusions, measures proposed in the reviews [25, 26].

10.2. Refractoriness to HLA-matched platelets in an adult (Japan, 2026)

A Japanese man in his fifties, with BSS diagnosed at 4 years from macrothrombocytopenia, absent ristocetin agglutination and GPIb-IX deficiency on flow cytometry, had received more than 200 units of platelets over 10 years and had anti-HLA antibodies [55]. After a fall, he developed a gluteal haematoma that required 4 surgical evacuations over 2 weeks, without haemostasis despite 10 units of standard platelets and 10 of HLA-matched platelets. He started eptacog alfa (activated) 90 µg/kg every 2 h on day 1, every 3 h on days 2 and 3 and 4 doses on day 4 (32 doses), with tranexamic acid 0.25 g every 8 h; the bleeding decreased after the first two doses, with no further surgery, platelets stable between 10 and 50 × 10⁹/L, D-dimers always ≤3 µg/mL and no thrombosis; he was discharged on day 42, without recurrence at 3 months [55]. Figure 1 of the paper (https://pmc.ncbi.nlm.nih.gov/articles/PMC12945955/figure/Fig1/) shows the course: platelets of about 32 × 10⁹/L on day 1, with a nadir of about 17 × 10⁹/L and fluctuations with the transfusions; haemoglobin of about 12 g/dL on day 1, falling to 6–7 g/dL between days 4 and 8 and stabilising at about 10–11 g/dL after eptacog alfa, given between approximately days 14 and 17 (values read from the graph). Figure 2 (https://pmc.ncbi.nlm.nih.gov/articles/PMC12945955/figure/Fig2/) documents the preoperative, intraoperative and postoperative findings and the haematoma specimen [55]. Eptacog alfa was used off-label, in an emergency, without prior ethics committee approval and with written consent, in a regimen based on the haemophilia trials and on BSS reports [55]. The case shows that refractoriness may extend to HLA-matched platelets and that eptacog alfa is the available alternative, but the 32-dose regimen does not constitute a standardised dose.

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

With education, appropriate care and prevention of trauma, patients with biallelic BSS have a “fairly normal” life, with a risk of severe bleeding with trauma, surgery and delivery [1, 15]. Life expectancy is usually normal, but bleeding affects quality of life [50]. In the Indian cohort, the annual bleeding rate in BSS was 1.85, against 11.85 in Glanzmann thrombasthenia, without deaths from bleeding among the 12 patients; more than 90% of the patients with either disease had no problems with mobility or self-care [51]. In the Pavia series, half of the biallelic patients had bleeding that was life-threatening or had a severe impact (grade 3 or 4) on quality of life [35]. The deaths described result from bleeding in children without a diagnosis or treatment, from cerebral haemorrhage or neonatal alloimmune thrombocytopenia and from underlying diseases in the acquired forms [41, 56, 59, 64]. Monoallelic BSS has a favourable prognosis: 58.2% of the Bolzano patients had no bleeding history [23].

11.2. Surveillance table

There is no surveillance protocol specific to BSS in the sources consulted. The table combines the recommendations of the BSS reviews with the protocol of the GeneReviews entry on MYH9-RD, transposed by extrapolation for the haematological items.

The extra-haematological items of MYH9-RD surveillance (audiogram, renal function, eye examination, liver enzymes) do not apply to BSS and serve only for the differential diagnosis [4].

12. Summary and Final Considerations

Bernard–Soulier syndrome results from the absence or dysfunction of the GPIb-IX-V complex, the receptor that binds platelets to subendothelial VWF and anchors them to the membrane skeleton; its loss produces at once an adhesion defect and macrothrombocytopenia. The biallelic, autosomal recessive form, due to variants in GP9, GP1BA or GP1BB (44%, 28% and 28% of 211 families), presents from childhood with mucocutaneous bleeding disproportionate to a moderately low count, with giant platelets, absent ristocetin agglutination not corrected by normal plasma and absence of CD42a and CD42b on flow cytometry; its prevalence is below 1 per million. The monoallelic, autosomal dominant form, due to variants in GP1BA or GP1BB, such as the founder variants Bolzano in Italy and Copenhagen in Denmark, is more frequent in referral cohorts, produces mild macrothrombocytopenia, often without bleeding, and is confirmed only by genetic testing, because aggregometry and flow cytometry may be normal.

The diagnosis depends on counting and measuring the platelets correctly, on not confusing the disease with ITP and on testing for the 22q11.2 deletion when the GP1BB variant appears homozygous or when a patient with the deletion has giant platelets. The differential diagnosis covers the class of inherited macrothrombocytopenias, headed by MYH9-RD, platelet-type and type 2B von Willebrand disease, acquired BSS and sitosterolaemia. Treatment is supportive and individualised: local measures, tranexamic acid, hormonal treatment of menorrhagia, desmopressin in selected cases and sparing transfusion of HLA-matched or leucodepleted platelets, with eptacog alfa (activated) as an off-label alternative in refractoriness and HSCT in severe refractory cases. In the monoallelic form, eltrombopag raises the count transiently. Pregnancy is the period of greatest risk, with postpartum haemorrhage in about half of the published deliveries and a risk of neonatal alloimmune thrombocytopenia, and requires a tertiary centre and a written plan. Gene therapy remains at the preclinical stage.

13. References

1. Lanza F. Bernard-Soulier syndrome (hemorrhagiparous thrombocytic dystrophy). Orphanet J Rare Dis. 2006;1:46. doi:10.1186/1750-1172-1-46. PMID: 17109744. PMC1660532.
2. BERNARD J, SOULIER JP. [On a new variety of congenital hemorragiparous thrombocytic dystrophy]. Bull Mem Soc Med Hop Paris. 1948;64(28-29):969-74. PMID: 18100454.
3. GeneGuidance. GP1BA — gene record and linked conditions (version dated 2026-09-26). Local project database; accessed on 2026-10-27.
4. Savoia A, Pecci A. MYH9-Related Disease. 2008 Nov 20 [updated 2021 Feb 18]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK2689/
5. Orphanet. Bernard-Soulier syndrome. ORPHA:274 [Internet]. Paris: INSERM; Orphadata rd-epidemiology and rd-natural_history of 23 Jun 2026; ORPHAcodes API of 2 Jul 2026. Available from: https://www.orpha.net/en/disease/detail/274
6. Orphanet. Isolated hereditary giant platelet disorder (group). ORPHA:220452 [Internet]. Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/220452
7. Martinez-Navajas G, Ceron-Hernandez J, Simon I, Lupiañez P, Diaz-McLynn S, Perales S, et al. Lentiviral gene therapy reverts GPIX expression and phenotype in Bernard-Soulier syndrome type C. Mol Ther Nucleic Acids. 2023;33:75-92. doi:10.1016/j.omtn.2023.06.008. PMID: 37416759. PMC10320622.
8. OMIM® Online Mendelian Inheritance in Man. #231200 BERNARD-SOULIER SYNDROME; BSS. Johns Hopkins University; last edited on 07/04/2026. https://omim.org/entry/231200. Accessed on 28 October 2026.
9. OMIM® Online Mendelian Inheritance in Man. #153670 BERNARD-SOULIER SYNDROME, TYPE A2, AUTOSOMAL DOMINANT; BSSA2. Johns Hopkins University; last edited on 05/01/2024. https://omim.org/entry/153670. Accessed on 28 October 2026.
10. Sivapalaratnam S, Westbury SK, Stephens JC, Greene D, Downes K, Kelly AM, et al. Rare variants in GP1BB are responsible for autosomal dominant macrothrombocytopenia. Blood. 2017;129(4):520-524. doi:10.1182/blood-2016-08-732248. PMID: 28064200. PMC6037295.
11. Orphanet. Pseudo-von Willebrand disease. ORPHA:52530 [Internet]. Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/52530
12. OMIM® Online Mendelian Inheritance in Man. #177820 VON WILLEBRAND DISEASE, PLATELET-TYPE; VWDP. Johns Hopkins University; last edited on 21/04/2026. https://omim.org/entry/177820. Accessed on 28 October 2026.
13. OMIM® Online Mendelian Inheritance in Man. *606672 GLYCOPROTEIN Ib, PLATELET, ALPHA POLYPEPTIDE; GP1BA. Johns Hopkins University; last edited on 10/12/2025. https://omim.org/entry/606672. Accessed on 28 October 2026.
14. OMIM® Online Mendelian Inheritance in Man. #258660 NONARTERITIC ANTERIOR ISCHEMIC OPTIC NEUROPATHY, SUSCEPTIBILITY TO; NAION. Johns Hopkins University; last edited on 20/12/2023. https://omim.org/entry/258660. Accessed on 30 October 2026.
15. GeneGuidance. GP1BB — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-27.
16. GeneGuidance. GP9 — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-27.
17. Freeman PJ, Hart RK, Gretton LJ, Brookes AJ, Dalgleish R. VariantValidator: accurate validation, mapping, and formatting of sequence variation descriptions. Hum Mutat. 2018;39(1):61-68. doi:10.1002/humu.23348. Tool accessed at https://rest.variantvalidator.org (GRCh38, mane_select) on 2026-10-27.
18. OMIM® Online Mendelian Inheritance in Man. *138720 GLYCOPROTEIN Ib, PLATELET, BETA POLYPEPTIDE; GP1BB. Johns Hopkins University; last edited on 04/08/2025. https://omim.org/entry/138720. Accessed on 28 October 2026.
19. OMIM® Online Mendelian Inheritance in Man. *173515 GLYCOPROTEIN IX, PLATELET; GP9. Johns Hopkins University; last edited on 04/08/2025. https://omim.org/entry/173515. Accessed on 28 October 2026.
20. Savoia A, Kunishima S, De Rocco D, Zieger B, Rand ML, Pujol-Moix N, et al. Spectrum of the mutations in Bernard-Soulier syndrome. Hum Mutat. 2014;35(9):1033-45. doi:10.1002/humu.22607. PMID: 24934643.
21. Kaya Z. Bernard-Soulier Syndrome: A Review of Epidemiology, Molecular Pathology, Clinical Features, Laboratory Diagnosis, and Therapeutic Management. Semin Thromb Hemost. 2025;51(2):209-218. doi:10.1055/s-0044-1789184. PMID: 39191409.
22. McDonald-McGinn DM, Hain HS, Emanuel BS, Zackai EH. 22q11.2 Deletion Syndrome. 1999 Sep 23 [updated 2020 Feb 27; revised 2025 May 8]. In: Adam MP, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1523/
23. Noris P, Perrotta S, Bottega R, Pecci A, Melazzini F, Civaschi E, et al. Clinical and laboratory features of 103 patients from 42 Italian families with inherited thrombocytopenia derived from the monoallelic Ala156Val mutation of GPIbα (Bolzano mutation). Haematologica. 2012;97(1):82-8. doi:10.3324/haematol.2011.050682. PMID: 21933849. PMC3248934.
24. Leinøe E, Brøns N, Rasmussen AØ, Gabrielaite M, Zaninetti C, Palankar R, et al. The Copenhagen founder variant GP1BA c.58T>G is the most frequent cause of inherited thrombocytopenia in Denmark. J Thromb Haemost. 2021;19(11):2884-2892. doi:10.1111/jth.15479. PMID: 34333846. PMC9292710.
25. Gresele P. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(2):314-22. doi:10.1111/jth.12792. PMID: 25403439.
26. Seligsohn U. Treatment of inherited platelet disorders. Haemophilia. 2012;18 Suppl 4:161-5. doi:10.1111/j.1365-2516.2012.02842.x. PMID: 22726101.
27. Novo Nordisk. NOVOSEVEN RT (coagulation factor VIIa, recombinant) [prescribing information]. Revised 07/2020. DailyMed setid ea65c32f-8518-4383-b621-17056c0eebc0. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=ea65c32f-8518-4383-b621-17056c0eebc0
28. Zaninetti C, Gresele P, Bertomoro A, Klersy C, De Candia E, Veneri D, et al. Eltrombopag for the treatment of inherited thrombocytopenias: a phase II clinical trial. Haematologica. 2020;105(3):820-828. doi:10.3324/haematol.2019.223966. PMID: 31273088. PMC7049343.
29. European Reference Network on Rare Hematological Diseases (ERN EuroBloodNet) [Internet] [cited 2026-10-27]. Available from: https://eurobloodnet.eu/
30. Grainger JD, Thachil J, Will AM. How we treat the platelet glycoprotein defects; Glanzmann thrombasthenia and Bernard Soulier syndrome in children and adults. Br J Haematol. 2018;182(5):621-632. doi:10.1111/bjh.15409. PMID: 30117143.
31. Berndt MC, Andrews RK. Bernard-Soulier syndrome. Haematologica. 2011;96(3). doi:10.3324/haematol.2010.039883
32. National Center for Biotechnology Information. ClinVar [Internet]. Bethesda (MD): NCBI. Records VCV000004156, VCV001677261, VCV000627039, VCV000013529, VCV001695035 [cited 2026-10-27]. Available from: https://www.ncbi.nlm.nih.gov/clinvar/
33. Ware J, Russell SR, Vicente V, Scharf RE, Tomer A, McMillan R, et al. Nonsense mutation in the glycoprotein Ib alpha coding sequence associated with Bernard-Soulier syndrome. Proc Natl Acad Sci U S A. 1990;87(5):2026-30. doi:10.1073/pnas.87.5.2026. PMID: 2308962. PMC53618.
34. Savoia A, Balduini CL, Savino M, Noris P, Del Vecchio M, Perrotta S, et al. Autosomal dominant macrothrombocytopenia in Italy is most frequently a type of heterozygous Bernard-Soulier syndrome. Blood. 2001;97(5):1330-5. doi:10.1182/blood.v97.5.1330. PMID: 11222377.
35. Savoia A, Pastore A, De Rocco D, Civaschi E, Di Stazio M, Bottega R, et al. Clinical and genetic aspects of Bernard-Soulier syndrome: searching for genotype/phenotype correlations. Haematologica. 2011;96(3):417-23. doi:10.3324/haematol.2010.032631. PMID: 21173099. PMC3046273.
36. Yaghoubi M, Sabeti N, Hajmollarezaei E. Successful Vaginal Delivery in a Pregnant Woman With Bernard-Soulier Syndrome: A Case Report. Clin Case Rep. 2026;14(2):e71706. doi:10.1002/ccr3.71706. PMID: 41669701. PMC12883334.
37. Orphanet. MYH9-related syndromic thrombocytopenia. ORPHA:182050 [Internet]. Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/182050
38. Orphanet. Autosomal dominant macrothrombocytopenia. ORPHA:140957 [Internet]. Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/140957
39. Orphanet. Severe autosomal recessive macrothrombocytopenia. ORPHA:438207 [Internet]. Paris: INSERM; 2026. Available from: https://www.orpha.net/en/disease/detail/438207
40. Andrews RK, Berndt MC. Bernard-Soulier syndrome: an update. Semin Thromb Hemost. 2013;39(6):656-62. doi:10.1055/s-0033-1353390. PMID: 23929303.
41. Salem ML, Zein E, Mohamed GS. Bernard-Soulier Syndrome: Identification of a Novel GP1BB Variant in a Mauritanian Patient. Mol Genet Genomic Med. 2026;14(1):e70186. doi:10.1002/mgg3.70186. PMID: 41566116. PMC12823461.
42. Ghodratnia E, Tabibian S, Barati M, Safa M. Molecular genetic diagnosis of Bernard-Soulier syndrome in Iranian patients: reporting three novel mutations. Transfus Apher Sci. 2026;65(4):104456. doi:10.1016/j.transci.2026.104456. PMID: 42229093.
43. Donnér M, Karpman D, Kristoffersson AC, Winqvist I, Holmberg L. Recurrent mutation Asn45-->Ser of glycoprotein IX in Bernard-Soulier syndrome. Eur J Haematol. 1996;57(2):178-9. doi:10.1111/j.1600-0609.1996.tb01357.x. PMID: 8856096.
44. Barozzi S, Pecci A, Marinoni M, Fontana G, Zanchetta ME, Noris P, et al. GP1BB c.179C > T is the most frequent cause of monoallelic Bernard-Soulier syndrome in the Italian population after the Bolzano variant: a report of two new families. Ann Hematol. 2023;102(3):677-679. doi:10.1007/s00277-022-05079-0. PMID: 36539614.
45. Nagoshi R, Sakamoto A, Imai T, Uchiyama T, Kaname T, Kunishima S, et al. Bernard-Soulier syndrome caused by a novel GP1BB variant and 22q11.2 deletion. Int J Hematol. 2024;120(1):142-145. doi:10.1007/s12185-024-03768-2. PMID: 38625506.
46. Urbański B, Urbańska Z, Bąbol-Pokora K, Subocz E, Młynarski W, Janczar S. Inherited or Immunological Thrombocytopenia: The Complex Nature of Platelet Disorders in 22q11.2 Deletion Syndrome. Semin Thromb Hemost. 2025;51(8):928-940. doi:10.1055/s-0044-1801383. PMID: 39805292.
47. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 624–627 (22q11 deletion syndrome).
48. Bartsch I, Sandrock K, Lanza F, Nurden P, Hainmann I, Pavlova A, et al. Deletion of human GP1BB and SEPT5 is associated with Bernard-Soulier syndrome, platelet secretion defect, polymicrogyria, and developmental delay. Thromb Haemost. 2011;106(3):475-83. doi:10.1160/TH11-05-0305. PMID: 21800012.
49. Strassel C, Bull A, Moog S, Receveur N, Mallo L, Mangin P, et al. Lentiviral gene rescue of a Bernard-Soulier mouse model to study platelet glycoprotein Ibβ function. J Thromb Haemost. 2016;14(7):1470-9. doi:10.1111/jth.13355. PMID: 27148783.
50. European Haemophilia Consortium. Bernard-Soulier syndrome [Internet]. Brussels: EHC; updated Jun 2026 [cited 2026-10-27]. Available from: https://www.ehc.eu/bleeding-disorder/bernard-soulier-syndrome/
51. Kharat SV, Kshirsagar S, Patil K, Saini GK, Jivani F, Kamble A, et al. Natural history & quality of life in Glanzmann thrombasthenia & Bernard Soulier syndrome: An observational study from India. Indian J Med Res. 2025;162(2):226-232. doi:10.25259/IJMR_141_2025. PMID: 41100648.
52. Citla-Sridhar D, Hu J, Sidonio RF Jr, Ahuja S. Bleeding Phenotypes in Inherited Platelet Function Disorders: Insights From the ATHNdataset. J Pediatr Hematol Oncol. 2026;48(5):207-216. doi:10.1097/MPH.0000000000003213. PMID: 42154520.
53. Orsini S, Noris P, Bury L, Heller PG, Santoro C, Kadir RA, et al. Bleeding risk of surgery and its prevention in patients with inherited platelet disorders. Haematologica. 2017;102(7):1192-1203. doi:10.3324/haematol.2016.160754. PMID: 28385783. PMC5566025.
54. Almatar E, Alsharidah S, Hashem OA. Recombinant Factor VIIa Prophylaxis in 2 Brothers with Bernard-Soulier Syndrome. Am J Case Rep. 2025;26:e949654. doi:10.12659/AJCR.949654. PMID: 41259294. PMC12684068.
55. Okamoto Y, Mizumoto C, Yamashita K, Inoue S, Saito S, Morimoto N, et al. Hemostatic rescue with rFVIIa in Bernard-Soulier syndrome refractory to HLA-matched platelet transfusion. Ann Hematol. 2026;105(4). doi:10.1007/s00277-026-06902-8. PMID: 41746364. PMC12945955.
56. Peitsidis P, Datta T, Pafilis I, Otomewo O, Tuddenham EG, Kadir RA. Bernard Soulier syndrome in pregnancy: a systematic review. Haemophilia. 2010;16(4):584-91. doi:10.1111/j.1365-2516.2009.02137.x. PMID: 20070385.
57. Sarıdoğan E, Onat T, Arda Düz S, Tuncay G, Abdurahmanova N, Orujova L, et al. Bernard-Soulier Syndrome from the Perspective of the Obstetrician: A Case Report with a Review of the Literature. Z Geburtshilfe Neonatol. 2023;227(3):168-178. doi:10.1055/a-2024-0819. PMID: 36889343.
58. Zibara V, Machin N. Inherited Platelet Disorders During Pregnancy and Delivery: Overview of Management Strategies and Emerging Therapeutic Considerations. Hematol Rep. 2026;18(2). doi:10.3390/hematolrep18020016. PMID: 41874099. PMC13010773.
59. Noris P, Schlegel N, Klersy C, Heller PG, Civaschi E, Pujol-Moix N, et al. Analysis of 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Haematologica. 2014;99(8):1387-94. doi:10.3324/haematol.2014.105924. PMID: 24763399. PMC4116839.
60. Agrawal M, Kamle A, Jain M, Chaudhary P, Malpani P. PEX6-Associated Heimler Syndrome 2 Presenting with Bernard-Soulier Syndrome. Indian Pediatr. 2026. doi:10.1007/s13312-026-00394-5. PMID: 42406288.
61. Gohda F, Uchiumi H, Handa H, Matsushima T, Tsukamoto N, Morita K, et al. Identification of inherited macrothrombocytopenias based on mean platelet volume among patients diagnosed with idiopathic thrombocytopenia. Thromb Res. 2007;119(6):741-6. doi:10.1016/j.thromres.2006.06.011. PMID: 16916536.
62. Jannat M, Basit AR, Khurram S, Jarral R, Qureshi MH. Bernard Soulier Syndrome Misdiagnosed and Treated as Immune Thrombocytopenia Purpura: A Case Report. Cureus. 2026;18(2):e103614. doi:10.7759/cureus.103614. PMID: 41853404. PMC12992152.
63. Alsharidah S, Almatar E, Lutfi R, Hashem OA. Coexistence of Immune Thrombocytopenic Purpura and Bernard-Soulier Syndrome: A Rare Pediatric Case Report. Int Med Case Rep J. 2025;18:1393-1397. doi:10.2147/IMCRJ.S537936. PMID: 41195296. PMC12584876.
64. Kamiya LJ, Morell MD, Marta RF, Narbaitz M, Marzac C, Goette NP, et al. Acquired Bernard-Soulier syndrome as the presenting feature of GATA2-related myeloid neoplasm in an adolescent: an insight into the mechanisms underlying the platelet defect. Haematologica. 2025;110(9):2240-2245. doi:10.3324/haematol.2025.287580. PMID: 40468948. PMC12399949.
65. Poon MC, d'Oiron R. Alloimmunization in Congenital Deficiencies of Platelet Surface Glycoproteins: Focus on Glanzmann's Thrombasthenia and Bernard-Soulier's Syndrome. Semin Thromb Hemost. 2018;44(6):604-614. doi:10.1055/s-0038-1648233. PMID: 29879742.
66. Gebetsberger J, Knöfler R, Streif W. "Diagnosis of Inherited Platelet Disorders": Update of the Interdisciplinary S2k-Guideline of the Permanent Pediatric Commission of the Society of Thrombosis and Haemostasis Research (GTH e.V.). Hamostaseologie. 2025;45(4):347-354. doi:10.1055/a-2628-5488. PMID: 40795927.
67. Parastatidou S, Sokou R, Lianou A, Tsante KA, Bikouli ED, Petrou E, et al. Guideline-based diagnosis and management of congenital platelet function disorders: Current insights and future directions. Blood Rev. 2026;76:101386. doi:10.1016/j.blre.2026.101386. PMID: 41832129.
68. Noris P, Klersy C, Zecca M, Arcaini L, Pecci A, Melazzini F, et al. Platelet size distinguishes between inherited macrothrombocytopenias and immune thrombocytopenia. J Thromb Haemost. 2009;7(12):2131-6. doi:10.1111/j.1538-7836.2009.03614.x. PMID: 19740094.
69. Zaninetti C, Bury L, Bozzi V, Zamora-Cánovas A, Althaus K, Uzun G, et al. Interlaboratory exercise on the use of immunofluorescence microscopy on the blood smear for recognizing inherited platelet disorders: Communication from the ISTH SSC Subcommittee on Platelets in Health and Disease. J Thromb Haemost. 2026;24(5):1923-1932. doi:10.1016/j.jtha.2026.02.012. PMID: 41791656.
70. Ferrari S, Regazzo D, Bertomoro A, Cerbo A, Galbiati A, Cosi E, et al. Clinical and Genetic Characterization of 269 Patients With Suspected Inherited Platelet Disorders: The Padua Monocentric Experience. Int J Lab Hematol. 2026;48(4):856-865. doi:10.1111/ijlh.70081. PMID: 41731342. PMC13357954.
71. Hayward CPM, Tasneem S. When it's not Glanzmann thrombasthenia or Bernard-Soulier syndrome: diagnosing other qualitative platelet disorders. Hematology Am Soc Hematol Educ Program. 2025;2025(1):137-146. doi:10.1182/hematology.2025000699. PMID: 41348029. PMC12891449.
72. Kaçar D, Altan M, Bayhan T, Yıldırım SF, Kurtipek FB, Arman Bilir Ö, et al. Clinical utility of a targeted next-generation sequencing panel for inherited platelet disorders in children. Diagnostics (Basel). 2025;15(17):2210. doi:10.3390/diagnostics15172210. PMID: 40941697. PMC12428363.
73. Marrero-Cepeda C, García-Donas G, Rodríguez-Martorell FJ, Núñez-Vázquez R, Prats-Martín C, Pérez-Simón JA, et al. From Bernard-Soulier syndrome to sitosterolemia: the role of genetic analysis in bleeding diathesis. Thromb J. 2025;23(1):84. doi:10.1186/s12959-025-00759-z. PMID: 41023734. PMC12477814.
74. OMIM® Online Mendelian Inheritance in Man. #273800 GLANZMANN THROMBASTHENIA 1; GT1. Johns Hopkins University; last edited on 06/04/2026. https://omim.org/entry/273800. Accessed on 30 October 2026.
75. OMIM® Online Mendelian Inheritance in Man. #619271 BLEEDING DISORDER, PLATELET-TYPE, 24; BDPLT24. Johns Hopkins University; last edited on 08/04/2026. https://omim.org/entry/619271. Accessed on 30 October 2026.
76. OMIM® Online Mendelian Inheritance in Man. #616176 BLEEDING DISORDER, PLATELET-TYPE, 19; BDPLT19. Johns Hopkins University; last edited on 07/04/2026. https://omim.org/entry/616176. Accessed on 30 October 2026.
77. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 36, section 36.1 (Disorders of Low Density Lipoprotein Metabolism — sitosterolaemia).
78. Saudubray JM, et al., editors. Inborn Metabolic Diseases. 7th ed. Berlin: Springer; 2022. Chapter 43, section 43.1 (Congenital Disorders of Protein N-Glycosylation).
79. Saudubray JM, et al., editors. Inborn Metabolic Diseases. 7th ed. Berlin: Springer; 2022. Chapter 44 (Disorders of Cellular Trafficking), sections 44.1.3 and 44.3.1.
80. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 50 (Deletion 11q syndrome — Jacobsen).
81. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 315 (Baraitser-Winter syndrome).
82. Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 8th ed. Philadelphia: Elsevier; 2022. p. 148 (Noonan syndrome).
83. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 514 (Noonan syndrome and RAS-MAPK syndromes).
84. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 545 (Orotic aciduria).
85. OMIM® Online Mendelian Inheritance in Man. #155100 MACROTHROMBOCYTOPENIA AND GRANULOCYTE INCLUSIONS WITH OR WITHOUT NEPHRITIS OR SENSORINEURAL HEARING LOSS; MATINS. Johns Hopkins University; last edited on 21/04/2026. https://omim.org/entry/155100. Accessed on 28 October 2026.
86. OMIM® Online Mendelian Inheritance in Man. #187800 BLEEDING DISORDER, PLATELET-TYPE, 16; BDPLT16. Johns Hopkins University; last edited on 07/04/2026. https://omim.org/entry/187800. Accessed on 28 October 2026.
87. OMIM® Online Mendelian Inheritance in Man. #147791 JACOBSEN SYNDROME; JBS. Johns Hopkins University; last edited on 03/04/2020. https://omim.org/entry/147791. Accessed on 28 October 2026.
88. OMIM® Online Mendelian Inheritance in Man. #615193 BLEEDING DISORDER, PLATELET-TYPE, 15; BDPLT15. Johns Hopkins University; last edited on 07/04/2026. https://omim.org/entry/615193. Accessed on 28 October 2026.
89. OMIM® Online Mendelian Inheritance in Man. #616737 TAKENOUCHI-KOSAKI SYNDROME; TKS. Johns Hopkins University; last edited on 05/08/2020. https://omim.org/entry/616737. Accessed on 28 October 2026.
90. OMIM® Online Mendelian Inheritance in Man. #124900 DEAFNESS, AUTOSOMAL DOMINANT 1, WITH OR WITHOUT THROMBOCYTOPENIA; DFNA1. Johns Hopkins University; last edited on 09/08/2024. https://omim.org/entry/124900. Accessed on 28 October 2026.
91. OMIM® Online Mendelian Inheritance in Man. #617443 BLEEDING DISORDER, PLATELET-TYPE, 21; BDPLT21. Johns Hopkins University; last edited on 08/04/2026. https://omim.org/entry/617443. Accessed on 28 October 2026.
92. OMIM® Online Mendelian Inheritance in Man. #187900 BLEEDING DISORDER, PLATELET-TYPE, 17; BDPLT17. Johns Hopkins University; last edited on 21/04/2026. https://omim.org/entry/187900. Accessed on 28 October 2026.
93. OMIM® Online Mendelian Inheritance in Man. #139090 GRAY PLATELET SYNDROME; GPS. Johns Hopkins University; last edited on 21/04/2026. https://omim.org/entry/139090. Accessed on 28 October 2026.
94. OMIM® Online Mendelian Inheritance in Man. #616913 BLEEDING DISORDER, PLATELET-TYPE, 20; BDPLT20. Johns Hopkins University; last edited on 07/04/2026. https://omim.org/entry/616913. Accessed on 28 October 2026.
95. OMIM® Online Mendelian Inheritance in Man. #613112 MACROTHROMBOCYTOPENIA, ISOLATED, 1, AUTOSOMAL DOMINANT; MACTHC1. Johns Hopkins University; last edited on 18/10/2023. https://omim.org/entry/613112. Accessed on 28 October 2026.
96. OMIM® Online Mendelian Inheritance in Man. #188025 THROMBOCYTOPENIA, PARIS-TROUSSEAU TYPE; TCPT. Johns Hopkins University; last edited on 04/08/2026. https://omim.org/entry/188025. Accessed on 28 October 2026.
97. OMIM® Online Mendelian Inheritance in Man. #616937 THROMBOCYTOPENIA 6; THC6. Johns Hopkins University; last edited on 04/05/2016. https://omim.org/entry/616937. Accessed on 28 October 2026.
98. OMIM® Online Mendelian Inheritance in Man. #620757 THROMBOCYTOPENIA 12 WITH OR WITHOUT MYOPATHY; THC12. Johns Hopkins University; last edited on 20/03/2024. https://omim.org/entry/620757. Accessed on 28 October 2026.
99. European Medicines Agency. NovoSeven (eptacog alfa [activated]): EPAR — product information, Summary of Product Characteristics in Portuguese [Internet]. Amsterdam: EMA; first authorisation 23 Feb 1996 [cited 2026-10-27]. Available from: https://www.ema.europa.eu/pt/documents/product-information/novoseven-epar-product-information_pt.pdf
100. INFARMED. Tafixyl 500 mg comprimidos revestidos por película (rev. 07/2026) and Tafixyl 100 mg/ml solução injetável (rev. 02/2026), tranexamic acid: Summaries of Product Characteristics [Internet]. Lisbon: INFARMED, Infomed; med_id 606502 and 584682 [cited 2026-10-27]. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=606502&tipo_doc=rcm
101. Pfizer Laboratories. CYKLOKAPRON (tranexamic acid injection) [prescribing information]. Effective 2025-09-03. DailyMed set_id 6e89a7d9-4da4-42aa-b7f8-c602c24eefe5. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=6e89a7d9-4da4-42aa-b7f8-c602c24eefe5
102. Agência Nacional de Vigilância Sanitária (ANVISA). Open data — medicines registered in Brazil (DADOS_ABERTOS_MEDICAMENTOS.csv) [Internet]. Brasília: ANVISA; downloaded on 2026-10-27. Records consulted: NovoSeven 117660012, Revolade 100681132, DDAVP 128760015, Transamin 156510045. Available from: https://dados.anvisa.gov.br/dados/DADOS_ABERTOS_MEDICAMENTOS.csv
103. INFARMED. Depo-Provera 150, 150 mg/ml suspensão injetável (medroxyprogesterone acetate): Summary of Product Characteristics [Internet]. Lisbon: INFARMED, Infomed [cited 2026-10-27]. Available from: https://extranet.infarmed.pt/INFOMED-fo/
104. INFARMED. Ddavp Desmopressin 0,004 mg/1 ml solução injetável (Ferring): Summary of Product Characteristics [Internet]. Lisbon: INFARMED, Infomed; med_id 2362 [cited 2026-10-27]. Available from: https://extranet.infarmed.pt/INFOMED-fo/download-ficheiro.xhtml?med_id=2362&tipo_doc=rcm
105. Ferring Pharmaceuticals. DDAVP (desmopressin acetate) injection [prescribing information]. Effective 2022-09-28. DailyMed set_id 651f6fee-a2c7-431b-8d5d-58b156c72244. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=651f6fee-a2c7-431b-8d5d-58b156c72244
106. Huisman EJ, Holle N, Schipperus M, Cnossen MH, de Haas M, Porcelijn L, et al. Should HLA and HPA-matched platelet transfusions for patients with Glanzmann Thrombasthenia or Bernard-Soulier syndrome be standardized care? A Dutch survey and recommendations. Transfusion. 2024;64(5):824-838. doi:10.1111/trf.17824. PMID: 38642032.
107. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine. NCT02422394, NCT03638817, NCT02324517, NCT07136857 [cited 2026-10-27]. Available from: https://clinicaltrials.gov/
108. Kashiwagi H. [Current diagnosis and treatment of congenital platelet function disorders: focus on Glanzmann thrombasthenia and Bernard-Soulier syndrome]. Rinsho Ketsueki. 2026;67(6):584-591. doi:10.11406/rinketsu.67.584. PMID: 42419992.
109. Zaninetti C. Thrombopoietin receptor agonists in inherited thrombocytopenias: an evolving mosaic of evidence. Res Pract Thromb Haemost. 2026;10(6):106907. doi:10.1016/j.rpth.2026.106907. PMID: 42703607. PMC13546829.
110. Oliveira M, Coutinho M, Cruz E, Morais S. Eltrombopag use in surgical procedures in inherited thrombocytopenia: expanding the role of thrombopoietin-receptor agonists. Res Pract Thromb Haemost. 2026;10(5):106861. doi:10.1016/j.rpth.2026.106861. PMID: 42620598. PMC13485643.
111. European Medicines Agency. Revolade (eltrombopag): EPAR — product information, Summary of Product Characteristics in Portuguese [Internet]. Amsterdam: EMA; first authorisation 11 Mar 2010 [cited 2026-10-27]. Available from: https://www.ema.europa.eu/pt/documents/product-information/revolade-epar-product-information_pt.pdf
112. Novartis. PROMACTA (eltrombopag) [prescribing information]. Effective 2025-12-18. DailyMed set_id 7714a0ed-34bb-46e6-a0a5-b363908b22c2. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7714a0ed-34bb-46e6-a0a5-b363908b22c2
113. de Oliveira M, Morais S. Advancing thrombopoietin receptor agonist therapy in inherited thrombocytopenia: new insights into avatrombopag use. Res Pract Thromb Haemost. 2026;10(6):106955. doi:10.1016/j.rpth.2026.106955. PMID: 42835379. PMC13635719.
114. Locatelli F, Rossi G, Balduini C. Hematopoietic stem-cell transplantation for the Bernard-Soulier syndrome. Ann Intern Med. 2003;138(1):79. doi:10.7326/0003-4819-138-1-200301070-00028. PMID: 12513061.
115. Rieger C, Rank A, Fiegl M, Tischer J, Schiel X, Ostermann H, et al. Allogeneic stem cell transplantation as a new treatment option for patients with severe Bernard-Soulier Syndrome. Thromb Haemost. 2006;95(1):190-1. PMID: 16543979.
116. Kanaji S, Kuether EL, Fahs SA, Schroeder JA, Ware J, Montgomery RR, et al. Correction of murine Bernard-Soulier syndrome by lentivirus-mediated gene therapy. Mol Ther. 2012;20(3):625-32. doi:10.1038/mt.2011.231. PMID: 22044935. PMC3293608.
117. Kanaji S, Fahs SA, Ware J, Montgomery RR, Shi Q. Non-myeloablative conditioning with busulfan before hematopoietic stem cell transplantation leads to phenotypic correction of murine Bernard-Soulier syndrome. J Thromb Haemost. 2014;12(10):1726-32. doi:10.1111/jth.12673. PMID: 25066812. PMC4194147.
118. Maaloul I, Charfi M, Ben Amor I, Mejdoub Y, Hsairi M, Safi F, et al. Congenital thrombopathies in southern Tunisia : A multicenter study. Tunis Med. 2025;103(11):1718-1723. doi:10.62438/tunismed.v103i11.6139. PMID: 41949971.
119. Touré SA, Faye A, Kaltam AYH, Sy D, Seck M, Diagne NK, et al. Diagnostic challenges in inherited platelet disorders in sub-Saharan Africa: first clinical case study of seven patients in Senegal. Blood Coagul Fibrinolysis. 2026;37(3):74-78. doi:10.1097/MBC.0000000000001408. PMID: 41630424.
120. World Federation of Hemophilia [Internet]. Montreal: WFH [cited 2026-10-27]. Available from: https://www.wfh.org/
121. Associação Portuguesa de Hemofilia e de outras Coagulopatias Congénitas [Internet] [cited 2026-10-27]. Available from: https://www.hemofilia.pt/