Glanzmann Thrombasthenia

An autosomal recessive inherited platelet disorder caused by quantitative or qualitative deficiency of platelet integrin αIIbβ3 (glycoprotein IIb/IIIa), with mucocutaneous bleeding, normal platelet count and morphology, and absent aggregation in response to all physiological agonists.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

1. Introduction

1.1. Original description and evolution of the concept

In 1918, the Swiss paediatrician Eduard Glanzmann described children with purpura and prolonged bleeding time whose platelets, normal in number and size, appeared isolated on the blood film rather than in clusters, and whose clots did not retract; he called the disease “hereditary haemorrhagic thrombasthenia”, meaning “weak” platelets [1, 3]. In 1956, Braunsteiner and Pakesch showed that these patients' platelets were of normal size but did not spread on surfaces or support clot retraction [1]. The introduction of aggregometry enabled Caen and Cousin, in 1962, and Caen and colleagues, in a series of 15 French patients published in 1964, to define absent aggregation in response to multiple agonists as the main diagnostic criterion [1, 3]. At that stage, the distinction was established between type I (absent aggregation and clot retraction) and type II (absent aggregation with residual retraction); “variant” forms, with near-normal amounts of dysfunctional receptor, were recognised in 1987 [1].

In 1974, Nurden and Caen demonstrated, by membrane glycoprotein electrophoresis, the selective absence of two major glycoproteins, later named GPIIb and GPIIIa; these were subsequently identified as the two subunits of a heterodimer of the integrin family, αIIbβ3 [1, 3]. Cloning of the ITGA2B and ITGB3 genes and description of the first founder variants, including the 11-base-pair deletion in ITGB3 in Iraqi Jews and the 13-base-pair deletion in ITGA2B in Arab families in Israel (Newman and colleagues, 1991), made GT the prototype of inherited integrin disorders [1, 14]. From 2018 onwards, the ClinGen Platelet Disorder Variant Curation Expert Panel adapted the American College of Medical Genetics and Genomics and Association for Molecular Pathology (ACMG/AMP) rules to these two genes [3].

1.2. Nomenclature and entities within scope

OMIM separates the disease by gene: Glanzmann thrombasthenia 1 (GT1, OMIM 273800), caused by biallelic ITGA2B variants, and Glanzmann thrombasthenia 2 (GT2, OMIM 619267), caused by biallelic ITGB3 variants; MedGen records BDPLT2 as a synonym for GT1 and BDPLT23 for GT2, within the “bleeding disorder, platelet-type” series [4, 5]. Orphanet combines both forms into a single entity, ORPHA:849, with autosomal recessive inheritance and neonatal or childhood onset [2]. The current textual definition in Orphanet attributes bleeding to “constitutional thrombocytopenia”; this wording contradicts OMIM, MedGen and the reference reviews, according to which platelet count and size are normal and the defect is functional (thrombasthenia), and should therefore not be reproduced [1–4].

Glanzmann thrombasthenia is defined as an autosomal recessive bleeding disorder caused by inherited defects of the membrane glycoprotein αIIbβ3, usually quantitative and sometimes qualitative, with absent or severely reduced platelet aggregation in response to all physiological agonists, normal platelet count and morphology, and reduced or absent αIIbβ3 expression on flow cytometry (or a receptor that is present but non-functional, in variant forms) [3, 10]. Residual αIIbβ3 expression distinguishes type I (<5%), type II (5–20%) and variant GT (≥20%, with a qualitative defect); the 2025 European practice review gives 5–30% for type II, a discrepancy reflecting the absence of a standardised threshold between laboratories, which does not alter management [10, 11]. Acquired GT, caused mainly by autoantibodies that inhibit normally expressed αIIbβ3, and leucocyte adhesion deficiency type III (LAD-III, FERMT3), which reproduces the aggregation pattern with normal receptor expression, belong to the immediate differential diagnosis but are not part of the entity [3, 10]. Allelic disorders of ITGA2B and ITGB3, with different mechanisms and inheritance patterns, are described in section 2.

1.3. The place of Glanzmann thrombasthenia among inherited platelet disorders

GT is the most frequent inherited platelet disorder among those presenting with mucocutaneous bleeding and, alongside Bernard–Soulier syndrome, the severe inherited platelet function disorder (IPFD) most readily identified in the laboratory, because absent aggregation in response to all agonists except ristocetin is almost exclusive to this disease [1, 18, 27]. αIIbβ3 deficiency was the first inherited integrin disorder to be characterised at the molecular level and remains the most frequent in that family [1]. The prospective international Glanzmann Thrombasthenia Registry (GTR), conducted between 2007 and 2011 in association with the authorisation of eptacog alfa (activated), provided the largest clinical treatment database, and the 2025 and 2026 surveys and studies of the European Association for Haemophilia and Allied Disorders (EAHAD) describe current European practice [11, 28–30].

2. Molecular Genetics and Pathophysiology

2.1. Integrin αIIbβ3: structure and function

Integrin αIIbβ3 is the most abundant receptor on the platelet surface, with approximately 50,000 copies per platelet, compared with approximately 50 copies of the vitronectin receptor αvβ3 [1]. The αIIb subunit is synthesised as a prepropeptide, cleaved into heavy and light chains linked by disulphide bonds; it associates with the β3 subunit in the megakaryocyte endoplasmic reticulum, and the heterodimer is transported to the platelet membrane [1, 6]. Unpaired or misfolded subunits are retained and degraded, explaining why loss of either chain removes the entire complex from the surface [1, 7]. ITGA2B is expressed only in the megakaryocytic lineage, whereas ITGB3 is widely expressed because β3 also forms the αvβ3 receptor in the endothelium, osteoblasts, smooth muscle and leucocytes [1, 7].

In resting platelets, αIIbβ3 has a bent, low-affinity conformation. Agonist activation triggers inside-out signalling involving protein kinase C, the guanine nucleotide exchange factor CalDAG-GEFI (encoded by RASGRP2), phosphatidylinositol 3-kinase and, as final regulators, talin and kindlin-3 (encoded by FERMT3), which bind to the β3 cytoplasmic tail and extend the receptor into its high-affinity conformation [1, 3]. Activated αIIbβ3 binds fibrinogen and, under high shear forces, von Willebrand factor (VWF), as well as fibronectin, vitronectin, CD40L and other ligands bearing the RGD motif; each fibrinogen molecule bridges two platelets and the aggregate grows [1, 6]. Ligand binding in turn generates outside-in signalling, responsible for further secretion, platelet spreading and clot retraction [3]. αIIbβ3 also binds erythrocyte ICAM-4, mediating adhesion between erythrocytes and platelets [6].

2.2. Physiological consequences of the defect

In GT, platelets change shape, adhere to the subendothelium through the GPIb-IX-V complex and VWF, and initiate secretion, but do not spread, aggregate or form the haemostatic thrombus [1]. Aggregation is absent in response to all physiological agonists (adenosine diphosphate [ADP], collagen, thrombin, arachidonic acid, adrenaline), whereas ristocetin-induced agglutination, which depends on VWF binding to GPIb rather than αIIbβ3, remains normal [3, 7]. Platelet fibrinogen content depends on the receptor and is absent in type I, and failure to bind the fibrin network prevents clot retraction [6, 7]. The resulting bleeding is mucocutaneous, as in other platelet disorders, rather than deep (joint or muscle bleeding), as in coagulation disorders [1, 31]. Glycoprotein VI, which binds fibrin and immobilised fibrinogen, has been proposed as a partial backup mechanism in the absence of αIIbβ3, and variants in other haemostasis or vascular wall genes may modulate severity [27].

Patients with β3 defects also lose the αvβ3 receptor in other tissues, but do not have more severe bleeding disease than patients with αIIb defects, and no consistent clinical consequences of this loss have been described [1, 3]. Studies in ethnic groups in Israel did not demonstrate protection against atherosclerosis, and GT does not protect against venous thrombosis either, including thromboembolism provoked by surgery, immobilisation or catheters [1, 32].

2.3. Molecular mechanisms and variant spectrum

GT requires biallelic pathogenic variants in the same gene; double heterozygosity, with one variant in ITGA2B and another in ITGB3, does not cause the disease, because each normal allele of each gene produces enough subunit to form approximately half the complex [3]. Compound heterozygosity predominates in populations without consanguinity; homozygosity predominates in consanguineous populations [3]. The phenotypes caused by the two genes are clinically indistinguishable, and only molecular testing identifies the gene [3, 6]. More variants have been described in ITGA2B (30 exons, a 1039-amino-acid protein) than in ITGB3 (15 exons, 788 amino acids), partly related to gene size; in an Italian series, 17 of 21 variants were in ITGA2B, whereas ITGB3 variants predominated in India, particularly in exon 4 [1, 3].

The spectrum includes missense, nonsense and splicing variants, small frameshift deletions and insertions and, rarely, large deletions [1]. The mechanisms fall into four categories: absent or reduced αIIb or β3 expression; abnormal folding, processing or intracellular transport of the complex, with endoplasmic reticulum retention; functional defects in the ligand-binding pocket or cytoplasmic domain; and locking of the receptor in an abnormal conformation [3]. Missense variants cluster in the αIIb β-propeller and the epidermal growth factor (EGF)-like domains of β3 [3]. Variant forms result from missense variants that allow receptor expression but impair fibrinogen binding or the conformational transition; the case described in section 10, with ITGB3 NM_000212.3:c.1199G>A, p.(Cys400Tyr), known in historical nomenclature as C374Y, illustrates this category [33–35].

Historical numbering of ITGB3 and ITGA2B variants counted amino acids from the mature protein, excluding the signal peptide (26 amino acids in β3), and therefore differs from current HGVS numbering, counted from the initial methionine; conversions should be obtained from VariantValidator or ClinVar and not calculated manually [34, 35]. The GT variant database contained approximately 100 variants in 2006; next-generation sequencing (NGS) has since accelerated genotyping and curation, and the ClinGen panel deposits variants classified with expert panel status in ClinVar [1, 3, 27].

2.4. Founder variants

Sources: [1, 7–9, 14, 15, 36, 37].

The Iraqi ITGB3 deletion and the Manouche ITGA2B splice variant have been confirmed in VariantValidator against the MANE Select transcripts and classified as pathogenic by an expert panel in ClinVar [8, 9, 36, 37]. The age and founder effect of the Manouche variant were estimated by Fiore and colleagues in 2011, and the variant is associated with a type I phenotype with complete absence of αIIbβ3, which has a direct consequence for the risk of alloimmunisation (section 7.8) [15, 38]. Rapid allele-specific restriction analysis tests have been described for these populations, but screening for a single ethnic variant may miss a different second allele in the same gene [1, 3]. The common nonsense variant in Tunisian patients is mentioned by GeneGuidance, based on Aloui and colleagues (2018), without HGVS nomenclature in the sources consulted [7].

2.5. Genotype–phenotype correlations, penetrance and modifiers

Penetrance of αIIbβ3 deficiency is complete at the laboratory level in biallelic carriers, but clinical expressivity is highly variable. There is little or no correlation between the amount of residual αIIbβ3 and severity: patients with no detectable αIIbβ3 may have minimal symptoms, whereas others with 10–15% receptor expression have severe bleeding, and the same variant may cause very different phenotypes in members of the same family [1, 7, 10]. Variant type and expression level do not predict severity, but do predict the risk of alloimmunisation: variants with premature termination codons and complete absence of αIIbβ3 were associated with anti-αIIbβ3 antibodies in 81% of transfused patients, compared with 25% with other variant types [3]. Coexisting mild von Willebrand disease worsens the bleeding tendency, and polymorphisms in immune system genes have been associated with a poorer response to transfusion and eptacog alfa (activated) [1, 39]. Heterozygotes for loss-of-function variants have approximately 50% αIIbβ3 and are generally asymptomatic [1].

2.6. Allelic disorders of ITGA2B and ITGB3

The same proteins give rise to three distinct clinical situations, which must not be confused when interpreting a genetic report [6]. The first is GT, caused by biallelic loss of function. The second is autosomal dominant macrothrombocytopenia caused by monoallelic gain-of-function variants, which keep αIIbβ3 constitutively activated and disrupt proplatelet formation: OMIM calls it “Glanzmann thrombasthenia-like with macrothrombocytopenia”, BDPLT16 (ITGA2B, OMIM 187800) and BDPLT24 (ITGB3, OMIM 619271); it is characterised by large platelets with anisocytosis, mild thrombocytopenia, mild functional abnormalities in vitro and absent or mild bleeding [3, 12, 13]. Most of these variants are in ITGB3, at the MIDAS, ADMIDAS and SyMBS metal cation-binding sites, and a minority are in ITGA2B, in the intracellular GFFKR sequence that keeps the receptor inactive [3]. For this reason, a heterozygous ITGB3 variant in a patient with large platelets should be interpreted in the context of this macrothrombocytopenia rather than as GT carrier status [7]. Orphanet groups these forms under “autosomal dominant macrothrombocytopenia” (ORPHA:140957), with a prevalence <1/1 000,000 [40].

The third situation is immunological: the human platelet antigen system HPA-1a/HPA-1b (PlA1/PlA2) is defined by the common p.Leu33Pro polymorphism (historical numbering, = NM_000212.3:c.176T>C p.(Leu59Pro)) in the β3 PSI domain and is the system most frequently implicated in fetal and neonatal alloimmune thrombocytopenia (FNAIT) in European populations; this occurs when an HPA-1b/1b mother is immunised by an HPA-1a-positive fetus, and maternal IgG crosses the placenta and destroys fetal platelets [7]. The BAK alloantigen of ITGA2B causes FNAIT by the same mechanism; the “autosomal dominant” label assigned by OMIM to these entries describes transmission of the paternal alloantigen rather than a disease in the carrier [6]. Post-transfusion purpura and an OMIM entry for susceptibility to myocardial infarction (608446) complete the ITGB3 associations [7]. FNAIT caused by anti-αIIbβ3 antibodies in a mother with GT is a different phenomenon, discussed in section 8.

3. Clinical Spectrum and Manifestations by System

3.1. General bleeding pattern

GT presents with spontaneous mucocutaneous bleeding and an exaggerated bleeding response to trauma, invasive procedures, menstruation and childbirth [1, 10]. Purpura, bruising, epistaxis, gingival bleeding and, in women, heavy menstrual bleeding (HMB) are almost constant; gastrointestinal bleeding and haematuria are less common but may be severe; deep visceral haematomas and spontaneous haemarthroses, typical of coagulation disorders, are rare [1, 3, 31, 41]. Severity ranges from minimal bruising to frequent, severe and potentially fatal bleeding, with no predictable relationship to the amount of residual αIIbβ3 [6, 10]. Bleeding scores, such as the International Society on Thrombosis and Haemostasis bleeding assessment tool (ISTH-BAT), have not been validated for inherited platelet disorders and have no established cut-offs in this population [3, 18]. The French PNDS makes the same caveat for platelet disorders, but considers the Higham score (the original pictorial chart, PBAC) sensitive for quantifying menstrual blood loss, with values above 100 strongly suggestive of HMB [17].

Some rare sites deserve specific recognition. Duodenal haematoma, spontaneous or after abdominal trauma, presents with periumbilical and right upper quadrant pain with vomiting; gastrointestinal angiodysplasias make gastrointestinal bleeding recurrent and difficult to control; haemoperitoneum from corpus luteum rupture presents with acute abdominal pain, sometimes with vaginal bleeding; and haemarthroses and deep haematomas are exceptional and almost always post-traumatic [17].

3.2. Frequency of manifestations in cohorts

The proportions vary according to study design: the reference series describe lifetime frequency, the GTR and Saultier review describe episodes prompting treatment, and the American study relies on diagnostic codes without laboratory confirmation, which may include misclassified patients [3, 16, 19]. A patient survey cited in the preclinical sutacimig study reports that approximately half of patients with GT report one bleeding episode per day [44].

3.3. Manifestations by age

Neonatal period and infancy. Symptoms may occur immediately after birth, as purpura, umbilical stump bleeding or excessive bleeding after heel prick for newborn screening; bleeding after circumcision is frequent in boys [10, 42]. In the Indian series, 26.6% of diagnoses were made at birth and 43.8% before 5 years of age [42].

Childhood. Most diagnoses are made before 5 years of age, prompted by easy bruising, epistaxis and gingival bleeding [3, 7]. Epistaxis is the most common cause of severe bleeding and is more severe in childhood; it may cause shock, as in the Spanish patient who started prophylaxis after epistaxis with shock at 11 years of age [1, 3, 39]. Shedding of deciduous teeth and dental extractions are frequent occasions for bleeding [10]. In the family of the clinical case in section 10, two siblings died at 3 years of age from severe epistaxis [33].

Adolescence and women of reproductive age. Menarche is a time of high risk of severe bleeding, because anovulatory cycles keep the endometrium under prolonged proliferative oestrogen stimulation; severe HMB may cause hypovolaemic shock, as in the 13-year-old Indian adolescent described in 2026 [1, 3, 45]. Almost all women with GT have HMB, and ovulatory bleeding (haemorrhagic corpus luteum) and endometriosis are reported by 53% and 30% of physicians surveyed by EAHAD [30]. Chronic iron deficiency is the most common consequence of repeated bleeding: all European centres surveyed observe it, and 77% observe it in at least half of women [30]. Pregnancy and childbirth are addressed in section 7.13.

Adulthood. Severity, except for menorrhagia and obstetric bleeding, tends to decrease with age; some patients reach adulthood without severe bleeding and are diagnosed late [3, 7]. Gastrointestinal bleeding, less common but potentially severe, and bleeding associated with surgery, procedures and trauma persist throughout life; in the review of cases treated with eptacog alfa (activated), 35.7% of patients were aged 18–44 years and 15.3% were aged 45 years or older [1, 43].

3.4. Disease forms and subtypes

Types I, II and variant GT cannot be reliably distinguished clinically; type I predominates in European series (78% in Paris, 70% in the Spanish registry) [1, 39]. The distinction matters for the risk of alloimmunisation, which is more frequent in type I with null variants, and for laboratory diagnosis, because variant forms may be missed by quantitative flow cytometry (section 5) [3, 38]. The phenotypes caused by ITGA2B and ITGB3 are indistinguishable [3].

3.5. Natural history without and with treatment

The Mumbai study shows the natural history in a setting with limited access: none of the 64 patients received eptacog alfa (activated), because of cost; whole blood (26.6%), fresh frozen plasma (32.8%) and platelet concentrate (40.6%) transfusions were frequently administered before definitive diagnosis; and between 2000 and 2025, 13 deaths from bleeding were recorded in patients with GT from the 64 families, 12 of which were attributed to treatment unavailability or inaccessibility [42]. In the American cohort, annualised mortality was 1222 per 100,000 patients, increasing with age and higher than in the general US population, with the limitation of being based on diagnostic codes [16]. With organised supportive care, the survival prognosis of diagnosed patients is good, and death from bleeding is rare outside severe trauma or intercurrent disease, although families frequently report siblings who died before diagnosis [1, 7]. In the EQ-5D questionnaire in the Indian study, more than 90% had no problems with mobility or self-care, 42.1% reported mild pain or discomfort and 31.6% mild anxiety or depression, with a weak negative correlation between ISTH-BAT and quality of life [42].

3.6. Non-bleeding complications

Alloimmunisation against αIIbβ3 and human leucocyte antigens (HLA) is the main iatrogenic complication, occurs after transfusions and pregnancies, and determines all subsequent treatment (section 7.8) [3, 46]. Treatment complications include infections transmitted by blood products and thrombosis associated with eptacog alfa (activated), catheters and immobilisation [28, 43]. GT does not protect against provoked venous thromboembolism: a 55-year-old woman developed bilateral pulmonary embolism two months after cervical discectomy with haemostatic cover [32].

4. Clinical Recognition and Warning Signs

4.1. When to suspect the disease

GT should be considered in anyone with disproportionate mucocutaneous bleeding and a normal platelet count, particularly when prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen and screening for von Willebrand disease are normal; a normal full blood count and normal coagulation screen do not exclude the disease [3, 7, 18]. Suspicion is strengthened by parental consanguinity, origin from a population with a known founder variant, siblings affected or deceased from childhood bleeding, and neonatal symptom onset [1, 33, 42]. The starting point recommended by the ISTH is a structured clinical assessment, with a personal and family history of bruising, epistaxis, menorrhagia, bleeding at childbirth, after invasive procedures and after dental extractions, with use of a bleeding assessment tool encouraged [18]. In the French pathway, suspicion may arise with the general practitioner or paediatrician (mucocutaneous bleeding with parental consanguinity, chronic iron deficiency, recurrent infections in LAD-III), the surgeon or anaesthetist (unexpected bleeding during surgery), the gynaecologist at menarche, the otorhinolaryngologist, the gastroenterologist, the dentist, the obstetric team after delivery or the geneticist; when the diagnosis is suspected, the patient is referred to a haemostasis centre, because a normal full blood count and routine haemostasis tests (PT, aPTT, fibrinogen and VWF) do not exclude the disease [17].

4.2. Warning signs and emergencies

The 2023 French consensus classifies emergencies into three groups: life-threatening blood loss (severe haemoglobin fall or shock; multiple trauma, psoas haematoma, deep wound, fracture, severe uterine bleeding, particularly at menarche, haematemesis or melaena, haemoptysis); bleeding that threatens functional outcomes (intracerebral, ocular, spinal haematoma, floor-of-mouth haematoma, compartment syndrome); and minor bleeding (moderate epistaxis, gynaecological or gingival bleeding, oral lesions, shedding deciduous teeth, dental extraction, suturing, sprain, dislocation, mild or moderate muscle haematoma, haemarthrosis, haematuria, arterial puncture) [10]. In epistaxis, swallowed or aspirated blood may mimic gastrointestinal bleeding or haemoptysis with respiratory distress, and posterior bleeding should be sought in the oropharynx, particularly in children [10]. The patient should carry an emergency card; in any of these situations, the emergency physician contacts the reference centre, requests pre-transfusion testing and orders components from the blood bank even if the patient is stable, and discharge is agreed with the expert [10]. The French PNDS defines what the attending physician should do when a patient bleeds: assess the systemic impact (blood pressure, heart rate, signs of anaemia), apply local measures if the site is accessible and, if these fail, are not possible or the general condition is affected, transfer the patient rapidly to a hospital with a specialist centre or, failing that, to the nearest competent emergency department, which contacts the reference physician [17]. Any suspicion of intracranial haemorrhage (sudden headache, nausea, vomiting, altered consciousness) requires immediate haemostatic treatment, without waiting for confirmation, continued according to the clinical course and to any planned invasive procedures [17].

4.3. Newborn screening

The sources consulted describe no newborn screening programme for GT. Diagnosis in newborns from affected families is made by molecular testing targeting the familial variant, because aggregometry requires large blood volumes and cord blood flow cytometry has been associated with bleeding risk when obtained by fetal puncture (section 8) [1, 3, 18]. A newborn of a mother with GT should have a platelet count because of the risk of FNAIT caused by maternal anti-αIIbβ3 antibodies [10, 48]. The French PNDS recommends considering GT or a related platelet disorder in a newborn with unexplained mucocutaneous bleeding, parental consanguinity and coagulation and VWF results normal for age; flow cytometry is particularly useful at this age because it requires little blood, and in the child of a mother with GT, cord blood allows a full blood count and platelet studies at birth (section 7.13) [17].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Diagnostic criteria

There are no formal scored criteria. Diagnosis rests on a combination of four elements: mucocutaneous bleeding; normal platelet count, size and morphology with normal routine coagulation; absent or severely reduced aggregation (usually <10%) in response to all physiological agonists with normal ristocetin-induced agglutination, confirmed in a second sample; and αIIbβ3 deficiency demonstrated by flow cytometry, or a receptor that is present but unable to activate in variant forms [1, 3, 10]. αIIbβ3 deficiency or dysfunction should always be confirmed and not inferred solely from the aggregation pattern; molecular confirmation identifies the gene and variants [3, 7]. The aggregation pattern, with abnormal clot retraction, is almost pathognomonic, but is shared by LAD-III and acquired GT [1, 3].

5.2. ISTH algorithm for inherited platelet function disorders

The Platelet Physiology Subcommittee of the ISTH Scientific and Standardization Committee (SSC) published an algorithm in 2015 derived from a worldwide survey and a consensus of ten experts, based on 14 relevant publications; it is not an evidence-graded guideline [18]. The 2013 recommendations for LTA standardisation resulted from a consensus using the RAND method, because of insufficient data for an evidence-based guideline, and cover preanalytical variables, collection, processing, agonists and reporting [49]. The 2011 British guideline for laboratory investigation of inherited platelet disorders and the 2025 update of the German and Austrian S2k guideline (GTH society, ThromKidplus group) propose similar algorithms; the S2k guideline includes standardised questionnaires, updated aggregometry and flow cytometry protocols, NGS, and restriction of diagnosis close to the patient's home to the essential steps [22, 24].

The ISTH recommends local reference intervals, validation by reagent batch and repetition of abnormal studies at least one month apart [18]. Clot retraction is assessed in non-anticoagulated whole blood, incubated for 60 minutes at 37 °C in a glass tube [18].

5.3. Laboratory tests: performance and limitations

Full blood count and blood film. Platelet count, size and granularity are normal; secondary iron deficiency manifests as low haemoglobin, microcytosis and increased red cell distribution width (RDW), and ferritin should be measured [3, 7]. Reduced numbers of large platelets point to macrothrombocytopenia caused by activating variants or to another macrothrombocytopenia [7].

Coagulation. PT, aPTT and fibrinogen are normal, except in acute consumptive coagulopathy; bleeding time is prolonged, but is not recommended by the ISTH because of poor reproducibility [3, 18].

Platelet function analyser (PFA-100). Closure time is markedly prolonged (>300 s), a compatible but non-specific finding shared by severe von Willebrand disease, Bernard–Soulier syndrome and afibrinogenaemia [3]. Sources differ regarding its role: Botero and colleagues, on behalf of the ClinGen panel, consider that a normal PFA-100 has a very high negative predictive value and virtually excludes GT, whereas the 2015 ISTH guidance does not recommend PFA-100 for screening platelet disorders because of insufficient sensitivity, specificity and reproducibility across IPFDs as a whole [3, 18]. These two positions can be reconciled by noting that the ISTH assesses the test for all platelet disorders, many of them mild, whereas GT produces extreme abnormalities; a normal PFA-100 makes GT unlikely but does not replace LTA when clinical suspicion is high. The French PNDS is aligned with the ISTH: because of their lack of specificity, it recommends neither the bleeding time nor the PFA closure time for the diagnosis of GT and related platelet disorders [17].

Light transmission aggregometry. This is the gold standard, used by 98% of European centres [3, 11]. The result is sensitive to preanalytical variables and should therefore be confirmed in a second sample [3, 49]. Whole blood impedance aggregometry has been compared with LTA, but there is insufficient evidence of equivalent sensitivity and reproducibility; it is useful when LTA is unavailable, provided the patient is referred at least once to a centre with LTA [3, 7]. The French PNDS does not recommend impedance aggregometry (Multiplate®) for diagnosis and requires characterisation by LTA and flow cytometry in a specialist centre; it describes, in GT and LAD-III, absent or markedly reduced aggregation in response to all agonists, even the strongest, with preserved agglutination by high-concentration ristocetin, and, in CalDAG-GEFI deficiency, absent aggregation at low agonist concentrations that is corrected at high concentrations [17].

Flow cytometry. Quantification of CD41 (αIIb) and CD61 (β3) in resting platelets confirms deficiency, distinguishes type I from type II and requires a small blood volume, allowing the sample to be sent over a distance; it is used by 96% of European centres [3, 7, 11]. Quantification alone does not identify variant forms with normal expression of a dysfunctional receptor, which are diagnosed by absent binding of activation-dependent antibodies (PAC-1) or fluorescein-labelled fibrinogen after stimulation [1, 3]. CD42a and CD42b flow cytometry excludes Bernard–Soulier syndrome, and normal β2-integrin flow cytometry, in a context of leucocytosis and infections, points to LAD-III [18, 50]. Total absence of receptor on flow cytometry identifies the patients at highest risk of anti-αIIbβ3 immunisation, which guides the choice of haemostatic treatment (section 7.8); in variant forms and related platelet disorders, in which the receptor is present, flow cytometry mainly seeks reduced activation capacity [17].

Western blot. This may indicate the affected gene through the presence of intracellular traces of αIIb or β3 or of unprocessed pro-αIIb, but is available in few centres (8% of European respondents use it, and 33% have no access to it) [1, 11].

5.4. Genetic testing

Genetic testing confirms the diagnosis, identifies the gene, allows carrier screening and reproductive counselling, and makes prenatal diagnosis and preimplantation genetic testing (PGT) possible [3]. The French PNDS recommends systematically offering molecular testing with four aims: to confirm the diagnosis, to help estimate the risk of anti-αIIbβ3 immunisation (truncating variants appear to predispose to it), to study segregation in relatives and detect heterozygotes, and to support reproductive plans; it stresses that, in the absence of an established genotype–bleeding phenotype correlation, the genetic result does not guide management of bleeding risk [17]. After LTA and flow cytometry, the ClinGen panel recommends sequencing only ITGA2B and ITGB3, rather than an extended panel; if two variants are not found, deletion and duplication analysis should be added [3]. Testing targeted to a founder variant is useful in populations with a known variant and consanguinity, but may miss a different second variant in the same gene; it is safer when both alleles have already been identified in an affected family member [1, 3]. ITGA2B and ITGB3 genotyping is performed by 88% of European centres [11]. The ISTH considers first-line exome sequencing conceivable, with the caveat that, without a well-defined phenotype, causality is difficult to prove except in well-characterised forms such as GT [18]. In IPFDs generally, mild bleeding may be a complex trait resulting from several heterozygous variants or from combination with type 1 von Willebrand disease [18].

Test limitations should be included in the interpretation: sequencing does not detect large deletions and duplications without specific copy-number analysis, and variants outside the regions analysed escape detection; a negative result, or a single variant, does not exclude GT when the laboratory phenotype is unequivocal [3]. One woman in the European pregnancy series had GT diagnosed by LTA without an identified coding pathogenic variant in ITGA2B or ITGB3 [48]. The report should specify the gene, reference transcript with version (NM_000419.5 for ITGA2B; NM_000212.3 for ITGB3), cDNA and protein HGVS nomenclature, zygosity, ACMG/AMP class and, for variants known by historical nomenclature, the correspondence confirmed in ClinVar [8, 9, 35]. The ClinGen panel specifications adapt ACMG/AMP allele-frequency criteria to disease prevalence, require a specific clinical and laboratory phenotype (absent aggregation with reduced αIIbβ3), and adjust segregation criteria; panel-curated variants appear in ClinVar with expert panel status [3]. For a variant of uncertain significance, confirmation of phase (parental testing), segregation with the aggregation and flow cytometry phenotype in the family, and correlation with the type of defect (expression versus function) guide reclassification [3].

Interpretation of an isolated heterozygous variant requires the phenotype: in a person with normal platelets and normal aggregation, it represents carrier status; in a person with macrothrombocytopenia, it may be an activating variant causing dominant disease [3, 7].

5.5. Carrier, prenatal and preimplantation diagnosis

αIIbβ3 quantification by flow cytometry shows approximately half the normal value in heterozygotes, but overlaps with the normal range and cannot reliably identify carriers; molecular testing is the indicated method [1]. Prenatal diagnosis by flow cytometry of fetal blood obtained by cordocentesis carries a high risk of bleeding and fetal loss and has been abandoned in favour of familial variant analysis in chorionic villus DNA; when the variants were unknown, polymorphic chromosome 17 markers were used [1]. PGT likewise requires identification of both familial variants [3].

5.6. European practice and resources

In the 2023 EAHAD survey (92 responses from 15 countries), 82% used the ISTH-BAT, 52% the pictorial blood assessment chart (PBAC) for menstrual bleeding and 30% the EQ-5D, although fewer than 40% considered them very suitable; 61% had access to urgent laboratory tests, and 73% included patients in a database [11]. ClinGen classified GT as strongly actionable in adults and children, supporting the reporting of pathogenic variants in these genes when found [6].

6. Differential Diagnosis

6.1. Principle of laboratory discrimination

GT is the only inherited platelet disorder with defective aggregation in response to all physiological agonists and normal ristocetin-induced agglutination [1]. Starting from this rule, the differential diagnosis is ordered by basic tests: normal ristocetin-induced agglutination and normal platelet size exclude Bernard–Soulier syndrome; a normal count excludes inherited thrombocytopenias; normal routine coagulation excludes afibrinogenaemia and von Willebrand disease with a substantial deficiency; defects restricted to ADP or collagen point to receptors or signalling; an impaired second wave in response to ADP and adrenaline points to dense granule or secretion defects; and an isolated defect in response to arachidonic acid points to a thromboxane A2 pathway defect or an aspirin effect [1]. When the aggregation pattern is that of GT but flow cytometry shows normal αIIbβ3, the possibilities are variant GT, LAD-III, RASGRP2-related platelet dysfunction and acquired GT [3, 50]. The French PNDS also includes in the differential drug-induced platelet dysfunction, certain forms of von Willebrand disease, factor XIII deficiency and fibrinolytic disorders, and regards acquired GT due to autoantibodies as exceptional [17].

6.2. Comparative table

6.3. Main differential diagnoses

LAD-III. Kindlin-3 deficiency prevents inside-out activation of β1, β2 and β3 integrins in all haematopoietic cells: the integrins are synthesised and expressed on the surface in normal amounts but do not activate, so the platelet has structurally normal αIIbβ3 that does not bind fibrinogen, and the neutrophil neither adheres nor migrates [50]. The aggregation pattern is identical to that of GT, but CD41/CD61 flow cytometry is normal, which is the key difference from types I and II [3, 50]. In a Turkish series of 12 patients, all born to consanguineous parents, presentation occurred at a median age of 18 days and diagnosis at 6 months; all had sepsis, 67% pneumonia, 25% omphalitis and 17% osteomyelitis, and the median leucocyte count on admission was 43,150/µL; three were initially diagnosed with juvenile myelomonocytic leukaemia and one with myelodysplastic syndrome [50]. Infants may have osteopetrosis [51, 60]. Allogeneic HSCT is the only curative treatment, because it corrects all three defects [50]. Orphanet records approximately 40 cases or families (ORPHA:99844) [64]. Any child with recurrent bacterial infections and a Glanzmann-type bleeding diathesis should be investigated for LAD-III, regardless of the leucocyte count [50].

RASGRP2-related platelet disorder. CalDAG-GEFI participates in the inside-out signalling that activates αIIbβ3 (section 2.1); its deficiency causes moderate to severe bleeding, with reduced aggregation mainly in response to ADP and adrenaline, normal αIIbβ3 expression and no leucocyte involvement [3]. RASGRP2, like FERMT3, is located on chromosome 11, and in France the two related entities (LAD-III and CalDAG-GEFI deficiency) together accounted for fewer than ten patients in 2019 [17].

Bernard–Soulier syndrome. In the biallelic form, the triad of giant platelets, absent ristocetin-induced agglutination and complete loss of GPIb-IX on flow cytometry identifies the disease; in a series of 211 families, variants were distributed across GP1BA (28%), GP1BB (28%) and GP9 (44%) [52]. The monoallelic form is milder and underdiagnosed; in a consecutive Danish cohort of inherited thrombocytopenias, 13% of patients had monoallelic Bernard–Soulier syndrome, with the Copenhagen founder variant GP1BA NM_000173.7:c.58T>G p.(Cys20Gly) being the most frequent cause of inherited thrombocytopenia in the country (Leinoe 2021, cited by GeneGuidance) [52]. Orphanet (ORPHA:274) estimates a prevalence <1/1 000,000 [65]. In the Mumbai study, 12 patients with Bernard–Soulier syndrome had a mean ABR of 1.85, compared with 11.85 in patients with GT, and none died [42].

Acquired GT. Absence of a family history and late onset of severe mucocutaneous bleeding with a normal or low count should prompt investigation for anti-αIIbβ3 autoantibodies, demonstrated by patient serum binding to normal platelets, and for underlying autoimmune, lymphoproliferative or plasma cell disease [1, 3]. Acute promyelocytic leukaemia with αIIbβ3 deficiency, sometimes with the t(15;17) breakpoint at 17q21, and GPIIb/IIIa antagonist drugs (abciximab, eptifibatide, tirofiban) complete this group [1, 3].

Macrothrombocytopenias. The main distinction is count and size: GT has normal platelets, whereas MYH9-related disease, Bernard–Soulier syndrome, grey platelet syndrome and activating ITGA2B/ITGB3 forms have large platelets [47]. The differential diagnosis table in GeneReviews for MYH9-related disease also includes 11q23 deletions (Jacobsen/Paris–Trousseau), ACTN1, CDC42, DIAPH1, FLI1, FLNA, GFI1B, GNE, SLFN14, SRC and TUBB1 [47]. Approximately 60% of index cases in the Italian registry of MYH9-related disease had a previous diagnosis of immune thrombocytopenia, and 30% received inappropriate treatments, including splenectomy; Orphanet places the prevalence of this disease in the 1–9/1 000,000 class (ORPHA:182050) [47, 66].

Granule and secretion defects. Grey platelet syndrome has a progressive course, with myelofibrosis and splenomegaly [53]. Hermansky–Pudlak syndrome combines bleeding with oculocutaneous albinism; α granules are normal and dense granules absent or severely deficient, and the HPS1 c.1472_1487dup16 variant (published designation, = NM_000195.5:c.1472_1487dup p.(His497GlnfsTer90)) accounts for approximately 80% of affected individuals in Puerto Rico [55]. RUNX1, ANKRD26 and ETV6 thrombocytopenias involve normal-sized platelets, a low count and a risk of haematological malignancy, which radically changes surveillance [56, 58, 59].

Metabolic causes. Cytosolic phospholipase A2α (cPLA2α) deficiency produces an aggregation defect in response to ADP and collagen that is fully corrected by adding arachidonic acid [61]. In glycogen storage disease type I, platelet dysfunction (abnormal adhesion, defective aggregation to collagen and adrenaline) is corrected by 24–48 hours of intravenous glucose or by desmopressin before surgery and reverses with good metabolic control [62, 63]. Platelet function disorders (including ITGA2B and ITGB3) also appear in the differential diagnosis of complete plasminogen activator inhibitor type 1 (PAI-1) deficiency, which causes bleeding after injury, surgery or dental procedures [67]. Chediak–Higashi syndrome combines mild bleeding, partial albinism and immunodeficiency [68].

7. Treatments and Risk Management Strategies

7.1. Status of recommendations

There is no specific international therapeutic guideline for GT: the EAHAD GT working group stated in 2025 that there is no European consensus on disease management [11]. The closest formal recommendation is the consensus from the French reference centre for inherited platelet disorders, developed in 2023 with the French Society of Emergency Medicine, patient associations and Orphanet, using methodology adapted from the Haute Autorité de Santé; it is based mainly on expert practice, with a low level of evidence [10]. The same reference centre coordinated the HAS PNDS (French National Diagnosis and Care Protocol), dated December 2019 and published in January 2020, which covers GT, LAD-III and CalDAG-GEFI deficiency and addresses diagnosis, treatment by bleeding site, pregnancy, the newborn, vaccination, school, follow-up and therapeutic education; it was developed by a multidisciplinary group with the Association Française des Hémophiles (AFH), without formal grading of evidence [17]. The British review of inherited platelet disorders with management guidelines, from the UK Haemophilia Centre Doctors' Organisation (UKHCDO), dates from 2006 and predates most GTR data [23]. The US and EU labels for eptacog alfa (activated), GTR data, the 2020 ClinGen panel review and EAHAD surveys complete the basis of this section [3, 11, 19, 20, 28, 30].

7.2. General measures

Patients should be followed at a centre experienced in bleeding disorders, with 24-hour contact availability, an emergency card or medical alert and a booklet containing their individual protocol; 87% of European centres recommend at least one annual consultation at the specialist centre [3, 10, 11]. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs), antiplatelet agents and anticoagulants should be avoided unless specifically indicated, as should the intramuscular route; analgesia uses paracetamol and, if necessary, strong analgesics [3, 10]. Urgent vaccines, such as tetanus vaccine, are administered subcutaneously in the deltoid region with a fine needle and prolonged compression; hepatitis B vaccination is recommended in inherited platelet disorders because of potential exposure to blood products [10, 53]. The French PNDS recommends the complete national vaccination schedule, particularly because of exposure to transfusions, usually by the subcutaneous route (less well tolerated and possibly less immunogenic, with no indication for post-vaccination serology), in the deltoid region with a fine 25 G needle followed by compression, and recording of the type and date of each vaccine [17]. Physical activity is recommended and adapted, with protective equipment, but contact and combat sports are strongly discouraged because of the risk of haematoma and post-traumatic cerebral haemorrhage; after an accident, the centre is contacted immediately [17]. In an emergency, peripheral venous access should be preferred, rectal temperature measurement avoided, and pre-transfusion testing and antiplatelet antibody testing requested immediately [10]. Oral health and correction of iron deficiency are part of routine management: 74% of European centres use long-term oral iron and 77% use intravenous iron in some patients [7, 11].

Iron deficiency. Iron deficiency requires a search for occult bleeding, particularly gynaecological or gastrointestinal; fatigue, hair loss, brittle nails and restless legs syndrome are warning signs [17]. Diagnosis is usually based on serum ferritin below 30 µg/L, often below 12 µg/L when anaemia is already present (thresholds that the PNDS text expresses, through a typographical error, in mg/L) [17]. The PNDS proposes oral iron, 325 mg/day in adults and 3–6 mg/kg/day in children, for 3–6 months to correct anaemia and replenish stores, without specifying whether the dose refers to the salt or to elemental iron; gastrointestinal intolerance often limits adherence, and intravenous iron is the alternative in cases of intolerance, poor response, need for rapid correction or malabsorption [17].

7.3. Local haemostatic measures

Compression is the first measure for any accessible bleeding; the French consensus recommends compression for at least 10 minutes with swabs that may be soaked in tranexamic acid, alcohol-free antiseptics and a compressive haemostatic dressing for skin wounds, and cryotherapy for 15–20 minutes every 6 hours [10]. For epistaxis, the patient sits semi-upright with the head tilted forwards, blows the nose to remove clots and applies compression with two fingers for at least 10 minutes, with ice; if this fails, bilateral anterior packing is performed using absorbable haemostatic material soaked in tranexamic acid, with antibiotics throughout the duration of packing and ear, nose and throat assessment, and a balloon or posterior packing if bleeding persists [10]. The PNDS adds prevention of recurrence (humidification of the environment, nasal saline instillations, petroleum jelly or a protective ointment on the mucosa), eight days of rest without closed-glottis straining after a significant epistaxis, and a later ear, nose and throat examination to treat any predisposing cause [17]. Compression and, if necessary, fibrin glue are used for shedding deciduous teeth and gingival bleeding [10]. For gingival bleeding, mouthwashes or local application of tranexamic acid, haemostatic sponges and iced-water mouthwashes with antiseptics are used, together with the oral antifibrinolytic; prevention depends on oral hygiene and dental review at least once a year [17]. Custom dental splints and gelatin with topical thrombin have been described as useful local measures [1].

Specific sites. Duodenal haematoma is usually managed conservatively, with haemostatic cover [17]. In gastrointestinal bleeding from angiodysplasias, the reference physician manages haemostatic treatment and the gastroenterologist the endoscopic treatment of the lesions; somatostatin analogues and antiangiogenic agents have been used, but the data are insufficient to recommend them [17]. Haematuria, which is uncommon, requires a search for a cause; first-line treatment is rest, hyperhydration, analgesics and antispasmodics, with haemostatic treatment reserved for strict necessity and antifibrinolytics avoided because of the risk of urinary tract obstruction by clots [17]. Intracranial haemorrhage requires immediate and prolonged haemostatic treatment (section 4.2), and haemoperitoneum from corpus luteum rupture requires rapid haemostatic treatment and sometimes surgery [17].

7.4. Antifibrinolytics

Tranexamic acid is used by 98% of European centres for surgery and is the mainstay of treatment for minor bleeding and an adjunct in all other bleeding [10, 11]. Its use in inherited platelet disorders is off-label [69]. In France it is marketed as Exacyl®. According to the PNDS, prophylaxis with tranexamic acid may reduce the frequency and recurrence of low-intensity bleeding; it is used alone, with local measures, or combined with or following platelets or rFVIIa; the oral dose is divided into 3–4 doses and reduced in renal impairment [17].

Tranexamic acid should be avoided in the event of recent thromboembolism, severe renal impairment (accumulation) and a history of seizures [10]. The PNDS draws attention to the rare thrombotic risk, which depends on the patient, the context, and the doses and duration of haemostatic agents, particularly in prolonged combination with rFVIIa [17]. In the GTR, an antifibrinolytic alone was effective in 84.7% of the 219 non-surgical bleeding episodes in which it was the sole treatment, and treatment failures occurred mainly in this group [29]. Aminocaproic acid is another antifibrinolytic used off-label in platelet disorders [43, 69].

7.5. Hormonal treatment of menstrual bleeding

HMB is associated with a proliferative endometrium due to oestrogen dominance; it has been treated with high-dose progesterone followed by a maintenance oral contraceptive [1]. The French consensus recommends gynaecological assessment and discussion of a monophasic pill containing at least 30 µg of ethinylestradiol, alongside oral tranexamic acid, avoidance of NSAIDs, treatment of iron deficiency and consideration of hospital admission if bleeding may require transfusion [10]. Severe HMB at menarche may require blood products, tranexamic acid and hormonal control, as in the 2026 Indian case in which ormeloxifene (a selective oestrogen receptor modulator available in India) and, long term, oral contraceptives were used; another report describes refractory HMB in an adolescent with GT, with a literature review [45, 70]. Stopping hormonal contraception to conceive exposes women to severe HMB and iron deficiency (section 7.13) [30].

The French PNDS structures the management of HMB: assess severity using the Higham score (above 100, HMB likely); prepare for menarche with a joint gynaecology, paediatric endocrinology and haemostasis consultation and a plan to prevent acute anaemia; treat severe HMB as an emergency, in hospital, with a high-dose combined oestrogen–progestogen and tranexamic acid, combined if necessary with platelets or rFVIIa, until bleeding stops; then continue a combined oestrogen–progestogen or a progestogen alone, with tranexamic acid from the first to the last day of menstruation when hormonal treatment is not possible or is insufficient; and reserve embolisation, endometrial thermal ablation or hysterectomy for uncontrollable life-threatening or disabling bleeding [17]. Secondary iron deficiency is screened for and treated regularly, and haemostasis and gynaecology review takes place at least every six months, more often around menarche [17].

7.6. Desmopressin

Desmopressin (DDAVP) has limited clinical utility in GT because it does not correct the αIIbβ3 defect: 71% of European centres never use it and 1% use it often [3, 11]. In the USA, its use in platelet disorders is off-label, because the desmopressin label is restricted to central diabetes insipidus, haemophilia A and type 1 von Willebrand disease with factor VIII above 5% [69]; the injectable label specifies 0.3 µg/kg by intravenous infusion, up to a maximum of 20 µg [71]. In Portugal, by contrast, the SmPC for injectable Ddavp Desmopressin® includes prolonged bleeding time in congenital platelet dysfunction, with 0.3–0.4 µg/kg by slow intravenous infusion (15–30 minutes), diluted in 50–100 mL of normal saline, reduced to 0.2 µg/kg in older people and in cardiovascular disease, and contraindicated in hyponatraemia [72]. The French SmPC for Minirin® specifies 0.3 µg/kg by the same form of infusion and includes unexplained prolonged bleeding time among its indications [73]. The 2006 review cited desmopressin as a measure to reduce platelet exposure, a position not followed in current European practice [1, 11].

7.7. Platelet transfusion

Platelet transfusion is the first-line treatment for severe bleeding and surgical cover in patients without refractoriness or antibodies, according to the US and EU labels for eptacog alfa (activated) [19, 74]. Its efficacy is limited by two factors: the patient's dysfunctional platelets, present in normal numbers, compete with the transfused platelets, so the required doses are higher than in thrombocytopenia (in a large series of congenital platelet disorders, the median transfusion dose was significantly higher in patients without thrombocytopenia); and alloimmunisation may render them ineffective [10]. The ClinGen panel therefore recommends reserving platelets for major surgery, life-threatening bleeding and significant bleeding unresponsive to other measures, and ideally avoiding them in women of reproductive age [3].

The French consensus recommends platelet concentrates one hour before surgery and then every 12–24 hours, and HLA-matched concentrates if necessary [10]. The 2020 PNDS specifies the product and dose: pooled platelet concentrates as first choice, HLA-matched apheresis concentrates if anti-HLA or anti-HPA antibodies are present, apheresis also in newborns and very young children, ABO compatibility always and RhD compatibility in women of reproductive age; usual dose of 0.5–0.7 × 10¹¹ platelets per 10 kg body weight (2015 HAS recommendation on platelet transfusion) and, in the neonatal period, 0.1–0.2 × 10¹¹ platelets/kg [17]. For minor surgery it proposes a single prophylactic transfusion one hour before, repeated according to the clinical course; for major surgery, a further transfusion according to the clinical course or routinely at hour 12, and transfusion support for 6–10 days after surgery, extended according to the bleeding course [17]. In European practice, 98% of centres use HLA-matched concentrates (32% routinely, 66% for specific indications), but access is limited in 48% and absent in 7%, and 61% have experienced being unable to obtain them in time [11]. For minor surgery, 79% of centres transfuse one preoperative concentrate and 89% do not routinely repeat it; for major surgery, 72% give at least two preoperative concentrates, with a routine second transfusion at 12 hours (10%) or 24 hours (37%) [11]. In the Netherlands, 75% of haematologists give HLA-matched platelets prophylactically in elective settings and 15% also match human platelet antigens (HPA) in GT, with the aim of preventing alloimmunisation and preserving the efficacy of random platelets for emergencies [75]. The safety of platelet therapy and changes in alloimmunisation status in the GTR were the subject of a specific registry analysis [76]. Transfusion recovery is assessed by count (96% of centres assessing it) and, in some centres, by CD41/CD61 flow cytometry of transfused platelets (29%), PFA (29%) or aggregation (17%) [11]. In resource-limited settings, such as India, HLA-matched and leucodepleted platelets are not feasible in most cases [42].

7.8. Alloimmunisation and refractoriness

Platelet transfusion and pregnancy can induce anti-HLA class I and anti-αIIbβ3 antibodies (isoantibodies directed against the receptor absent in the patient), which bind to transfused platelets, interfere with their function and reduce their survival [46, 77]. Prevalence estimates vary with population and definition: 20–30% of patients according to the French consensus; up to 30% according to the ClinGen panel; 25–50% of multiply transfused patients according to the Saultier review; anti-HLA in 17–23% and anti-αIIbβ3 in 20–30% according to the 2025 pregnancy review; and 25–70% in Indian series [3, 10, 42, 43, 48]. The French multicentre prospective study of 55 patients followed between 2018 and 2025 found anti-αIIbβ3 antibodies (monoclonal antibody immobilisation of platelet antigens technique, MAIPA) in 36%, mainly in patients with type I GT, complete absence of αIIbβ3 and biallelic null variants, particularly the Manouche variant ITGA2B c.1544+1G>A; antibodies appeared up to four weeks after transfusion and were transient in most patients, disappearing within 18 months, whereas anti-HLA antibodies (Luminex technique), present in approximately 25–30%, were more persistent [38]. Sera containing anti-αIIbβ3 reduced fibrinogen binding to donor platelets without complement-mediated injury, explaining the functional ineffectiveness of transfusions [38]. The antibodies are directed mainly against β3, and the endothelial αvβ3 receptor has been recognised as an additional target [77].

Monitoring is the main preventive measure: the French consensus recommends testing for antiplatelet antibodies on the day of admission and 1–3 months after any blood product administration [10]. The PNDS recommends testing for anti-HLA and anti-HPA antibodies at the initial work-up and before any transfusion and, if positive, determining the patient's HLA-A and HLA-B phenotype and HPA genotype to allow compatible platelets; anti-αIIbβ3 antibodies are tested for by the reference MAIPA method, before and 1–3 months after each transfusion, because the simpler ELISA and Luminex® assays have not been evaluated in this setting [17]. The same text stresses that the presence of antibodies does not always predict transfusion ineffectiveness and is not, in itself, a contraindication to platelets; that ineffectiveness has no defined criteria and is assessed by persistence of bleeding and by haemoglobin and platelet count; and that, in forms lacking the receptor, flow cytometry quantifies circulating transfused platelets [17]. Truncating variants of ITGA2B or ITGB3 are identified as a possible risk factor for immunisation, in line with the French prospective study [17, 38]. In Europe, 89% of centres monitor anti-HLA antibodies and 90% perform HLA class I typing, but only 48% regularly screen for anti-αIIbβ3 (81% in France compared with 53% or less in other countries); the preferred method is indirect MAIPA (58%), followed by enzyme-linked immunosorbent assay (ELISA), flow cytometry and the Luminex technique [11]. Transfusion ineffectiveness is defined by clinical ineffectiveness despite sufficient volume (79% of centres), an insufficient increment (45%) or an insufficient proportion of αIIbβ3-positive platelets on flow cytometry (13%) [11]. The definition of refractoriness used in the GTR studies and the Saultier review is bleeding during surgery despite adequate transfusion and/or persistence or recurrence of bleeding within the following 24 hours [43]. With anti-HLA antibodies, HLA-matched donors are used, although they are not always available in emergencies; with anti-αIIbβ3 antibodies, the strategy is to use eptacog alfa (activated) and reduce platelet exposure [39, 46]. Antibody removal by protein A immunoadsorption before surgery at specialist centres provides transient relief, and an isolated report has been published of imlifidase use in a child with anti-GPIIb/IIIa and anti-HLA antibodies and severe refractoriness after HSCT [1, 77, 78]. The TAAS trial (NCT04595617, Bordeaux, completed) studied genetic, therapeutic and sociodemographic risk factors for anti-αIIbβ3 immunisation after transfusion or pregnancy, with no results in the registry [79].

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

Mechanism. At pharmacological concentrations, recombinant activated factor VII (rFVIIa) binds to the surface of activated platelets and directly activates factor X independently of tissue factor; the resulting thrombin burst generates fibrin that increases adhesion and aggregation of thrombasthenic platelets through an αIIbβ3-independent pathway, produces a more stable and less permeable clot, and activates thrombin-activatable fibrinolysis inhibitor (TAFI), reducing lysis [1, 28]. The systemic half-life is 2–3 hours and affinity for activated platelets is low, requiring repeated doses of 90–270 µg/kg, with plasma peaks of 25–75 nM [44].

Presentation. NovoSeven® RT (USA) is a room-temperature-stable lyophilised powder in single-dose vials of 1, 2, 5 and 8 mg, reconstituted with L-histidine solvent to approximately 1 mg/mL and administered as an intravenous bolus within 3 hours of reconstitution [19]. In the EU, the medicine is NovoSeven® (eptacog alfa [activated]), from Novo Nordisk A/S [20]. The European summary of product characteristics (SmPC) recommends bolus administration because continuous infusion has been associated with lack of efficacy [74].

Table sources: [19, 20, 74].

Neither the US label nor the European SmPC defines a maximum per-administration or cumulative dose in GT; the SmPC advises against intentionally increasing the regimen above the recommended doses, because of a lack of information on the additional risk, and states that in the observational registry of 133 patients the median dose per infusion was 90 µg/kg (range 28–450 µg/kg) in the 333 bleeding episodes and 92 µg/kg (up to 270 µg/kg) in the 157 surgical procedures [19, 20]. The PNDS adds that there is no laboratory test to monitor efficacy, which is judged only by cessation of bleeding; that off-label use is discussed mainly in young patients at high risk of anti-αIIbβ3 immunisation and in women of reproductive age, because of the risk posed by antibodies in a future pregnancy; that combination with tranexamic acid is possible, with monitoring of thrombotic risk if prolonged; and that rFVIIa is not authorised for the related platelet disorders (LAD-III and CalDAG-GEFI deficiency) [17].

In the paediatric GTR, the median dose was 90 µg/kg for non-surgical bleeding, with more doses and a higher cumulative dose for severe bleeding (median 5.5 doses and 532.5 µg/kg) than for moderate bleeding (median 2 doses and 180 µg/kg); for surgical procedures in patients with antibodies and refractoriness, a median dose of 200 µg/kg at 2-hour intervals was used [80]. In the review of 100 patients, the median dose per administration was 90 µg/kg, with a median interval of 2 hours and a median cumulative dose of 270 µg/kg for non-surgical bleeding; for major surgery, the median cumulative dose was 270 µg/kg without antibodies and 500 µg/kg with antibodies [43].

Adverse effects. The US label carries a boxed warning about serious arterial and venous thrombotic events; risk increases with concomitant activated prothrombin complex concentrate (aPCC), other haemostatic agents, cardiovascular disease and thrombotic predisposition, and the dose should be reduced or stopped if intravascular coagulation or thrombosis occurs [19]. There is a risk of hypersensitivity and anaphylaxis, greater in people allergic to mouse, hamster or bovine proteins; the label lists no contraindications [19]. Among the 140 patients with GT and 518 episodes in the GTR and the Hemostasis and Thrombosis Research Society (HTRS) registry, one deep vein thrombosis, two headaches, two fevers, one episode of nausea and one episode of dyspnoea were recorded [19]. In a database of 12,288 episodes and reports to the FDA Adverse Event Reporting System (FAERS), the overall thrombosis rate in patients with GT treated with rFVIIa was 0.19% [43]. The systematic review of cases identified four serious adverse events (2.7% of treatments), all thromboembolic and occurring with additional factors: a fatal pulmonary embolism in a 30-year-old woman with diffuse alveolar haemorrhage who also received aminocaproic acid and multiple transfusions; a deep vein thrombosis and pulmonary embolism in a 72-year-old woman receiving continuous infusion at 30 µg/kg/h for 15 days and tranexamic acid; and two catheter-associated thromboses, in a 2-year-old child and a 48-year-old woman after neurosurgery [43]. In the surgical GTR, one of four rFVIIa-related adverse events was a non-fatal thromboembolism in an adult woman treated with rFVIIa, platelets and an antifibrinolytic [81]. Monitoring includes signs of thrombosis, individualised thromboprophylaxis and avoidance of unnecessary central catheters [10, 77].

7.10. Comparative regulatory status

The EMA European public assessment report (EPAR) page still retains the old indication wording, which required antibodies, alongside the current wording, potentially causing confusion when consulted; the current SmPC uses the wording without an antibody requirement [20, 74]. In France, the PNDS refers to the European marketing authorisation for refractory or immunised patients and asks that the justification for any off-label use be recorded in the medical record [17]. The sources consulted do not include reimbursement or national access data for Portugal or Brazil.

7.11. Evidence on haemostatic treatment

These data come from observational registries and case reports, without randomised trials; the GTR was not designed to select doses or compare modalities, and treatment choice depended on severity, immunological status and local availability [19, 28]. Success rates across modalities are not comparable, because severe bleeding and patients with antibodies more often received combined treatments, explaining why the rFVIIa–platelet combination has the lowest rate [29, 80]. Reviews of published cases overestimate success through publication bias, and the definition of efficacy varies between sources (bleeding stopped within 6 hours in the European SmPC registry, adjudicated assessment in the GTR) [43, 74]. The secondary prophylaxis study includes four patients, without a control group and with non-protocolised selection, and the relative reduction of 57% corresponds to a baseline median ABR of 3 [39]. The sources consulted did not identify published negative trials in GT; the marzeptacog alfa (activated) trial, which included patients with GT, was terminated by company decision without registry results (section 7.16) [84].

7.12. Regular prophylaxis and early rFVIIa use

Regular rFVIIa prophylaxis is off-label and reserved for patients with recurrent severe bleeding, particularly refractory patients: in the Spanish registry, 4 of 37 patients received 90 µg/kg, three twice weekly and one woman monthly, aligned with her menstrual cycle; 75% discontinued the antifibrinolytic and ferritin increased [39]. Low-dose weekly regimens and regimens in adolescents with recurrent haemarthroses have also been reported [39]. Several authors propose extending the indication to patients without antibodies and using rFVIIa early to reduce platelet exposure and the risk of alloimmunisation, with relevance to future pregnancies and potential HSCT; this is a proposal rather than an approved indication [39, 43]. In Europe, 79% of centres often or always consider off-label rFVIIa in patients without immunisation or refractoriness, particularly in women wishing to become pregnant and for surgical cover, and 69% combine it with platelets [11]. In the GTR, rFVIIa was used in 516 of the 829 bleeding episodes and in 89 of the 206 procedures in patients without confirmed antibodies or refractoriness [11].

7.13. Pregnancy, delivery and puerperium

Risks. Pregnancy in a woman with GT carries maternal risks (severe HMB and iron deficiency after stopping contraception, bleeding after assisted reproduction procedures, bleeding after miscarriage or abortion, primary and secondary postpartum haemorrhage [PPH], alloimmunisation) and risks to the child (pregnancy loss, FNAIT, fetal intracranial haemorrhage and inheritance) [30]. In a 2011 systematic review cited by EAHAD, PPH occurred in 34% of women with GT, compared with 6.4% in the general Dutch population [30]. The 2025 review, which combined 173 published pregnancies and a series of eight women from three European centres (2017–2024), found PPH in 84 of 145 deliveries (60%): primary in 31%, secondary in 14%, both in 4% and unspecified in 8%; mean blood loss was 1115 mL (100–6000 mL; n=27), and primary PPH required red cell transfusion in 56%, platelets in 42% and rFVIIa in 22% [48]. The difference between 34% and 60% reflects different denominators and periods and publication bias in case reports [30, 48]. Secondary PPH occurred between 3 days and 3 weeks after delivery [48]. Miscarriages (15%) were comparable to those in the general population [48]. Approximately half of pregnant women with GT may be unaware of the diagnosis, given the phenotypic variability [3].

Fertility. Medically assisted reproduction (MAR) was required in 11 of 22 pregnancies (50%) with a described mode of conception, compared with infertility of 17.5% in the general population; ovarian bleeding and endometriosis are the proposed factors [48]. In vitro fertilisation and intracytoplasmic sperm injection were performed safely, but oocyte retrieval was complicated by bleeding in 1 of 3 cases with reported outcomes, and haemostatic cover was heterogeneous [48]. Delays in conception of more than one year after stopping contraception were reported by 62% of physicians surveyed [30].

Preconception. Preconception counselling is recommended (95% of respondents), ideally in a joint obstetric and haematology clinic, which exists in only 24% of centres [30]. Usual preconception tests are full blood count and ferritin (91%), anti-HLA antibodies (70%) and anti-αIIbβ3 antibodies (58%) [30]. Partner carrier screening is recommended by all authors where there is consanguinity (section 8) [3, 48]. To treat bleeding in women wishing to become pregnant, 94% of respondents prefer rFVIIa to platelets to avoid alloimmunisation, and 79% would consider advising against pregnancy in selected cases, particularly with a severe bleeding phenotype [30]. The French PNDS recommends that the preconception consultation, ideally multidisciplinary, take place before hormonal treatment is stopped, in order to shorten the period of gynaecological bleeding, offer fertility investigations if necessary and explain maternal and fetal risks to the couple; follow-up is planned between the gynaecologist and the haemostasis specialist, with protocols for bleeding, anaemia screening, antibody surveillance and the ultrasound schedule, and the mandatory anaesthetic consultation is brought forward to the 7th month, immediately after the third-trimester scan, instead of the usual 8th month [17]. In a spontaneous miscarriage, surgical aspiration under general anaesthesia is preferred, with misoprostol discussed according to sac size and gestational age; in an ectopic pregnancy, bleeding risk weighs in the choice of treatment [17].

Antibody surveillance in pregnancy. Anti-HLA or anti-αIIbβ3 antibodies have been described in up to 70% of pregnant women with GT [3]. In the 2025 review, antibodies were tested in only 59 of the 173 pregnancies (34%): anti-HLA in 15%, anti-αIIbβ3 in 12%, both in 8% and an unspecified type in 8% [48]. In 37 pregnancies with known antibody status, neonatal complications occurred in 45% of the 22 women with antibodies and in none of the 15 without antibodies [48]. Green-top Guideline No. 71 of the Royal College of Obstetricians and Gynaecologists (RCOG), jointly with the UKHCDO (2017), recommends, according to the EAHAD synthesis, testing anti-αIIbβ3 antibodies at the first visit, at 28 and at 34 weeks, giving intravenous immunoglobulin (IVIg) to women with high or rising titres or a previous child affected by FNAIT, giving tranexamic acid to all women at delivery and avoiding neuraxial anaesthesia; it does not recommend anti-HLA screening in pregnancy or postpartum screening [30]. In practice, 94% of respondents screen for anti-HLA and 91% for anti-αIIbβ3, on variable schedules, and 63% would recommend IVIg to prevent FNAIT in selected situations [30]. In published IVIg reports, five pregnancies resulted in healthy newborns (including twins) and one in FNAIT without bleeding [48]. The French PNDS recommends testing for anti-αIIbβ3 antibodies at the start of pregnancy and regularly thereafter; if they are present, more frequent obstetric ultrasound scans to detect fetal intracranial haemorrhage and IVIg from 18 weeks of gestation, at a dose of 1 g/kg per week, with or without corticosteroids, may be discussed [17]. The indication for IVIg is thus broader than in the RCOG/UKHCDO guideline, which reserves it for high or rising titres or previous FNAIT (section 7.18) [17, 30].

Treatment of bleeding during pregnancy. European physicians use tranexamic acid (79%), rFVIIa (67%), HLA-matched platelets (46%), random platelets (21%) and desmopressin (6%) [30].

Delivery. Delivery should take place in a maternity unit with adequate support and access to blood products; the route is decided on obstetric grounds (75% of respondents), and caesarean section may be preferable for organisational reasons, in FNAIT or when the fetus is at risk of GT, to avoid instrumentation [10, 30, 48]. In published pregnancies, 53% of deliveries were vaginal and 47% by caesarean section, and general anaesthesia was used in 91% of the 11 caesarean sections with documented anaesthesia [48]. Neuraxial anaesthesia (epidural or spinal) is considered contraindicated by the French consensus, the ClinGen panel and 69% of respondents (85% of those with experience), even with haemostatic cover [3, 10, 30]. In the absence of a prior protocol, the French consensus recommends similar management for vaginal delivery and caesarean section, with platelet concentrates and/or rFVIIa, with or without tranexamic acid, drains for caesarean section, serial haemoglobin measurements during the first 12–24 hours and routine assisted placental delivery; antibody testing is performed on admission without waiting for the result before starting treatment [10]. The ClinGen panel describes rFVIIa with antifibrinolytics for vaginal delivery and the option of adding platelets for caesarean section [3]. The PNDS specifies a level 3 or 2B maternity unit and routine active management of the third stage of labour to prevent PPH, and considers formally contraindicated, in addition to neuraxial anaesthesia, peripheral blocks (transversus abdominis plane block, pudendal block) and intramuscular analgesics; initial haemostatic cover is identical for vaginal delivery and caesarean section, with platelets or rFVIIa supplemented by tranexamic acid, chosen according to previous transfusion efficacy, antibodies and the risk of venous thrombosis [17]. Postpartum surveillance lasts at least 4 weeks, but the patient should know that the bleeding risk may persist for up to 8 weeks; tranexamic acid prevents secondary PPH, and progestogen-only or combined oestrogen–progestogen hormonal treatment is offered after delivery, depending on breastfeeding [17].

Sources: [30, 48].

Neonatal outcome. Among 149 children from 143 published pregnancies, 32 (22%) had complications: five stillbirths (four due to intracranial haemorrhage), one neonatal death, 17 cases of FNAIT and nine neonatal bleeding episodes [48]. The newborn of a mother with GT without consanguinity is generally an asymptomatic heterozygote, but is exposed to FNAIT through transplacental passage of maternal anti-αIIbβ3 antibodies; the 2025 review recommends platelet counts in all newborns [10, 48]. Antibodies may appear only after delivery, as in the woman in the European series in whom anti-αIIbβ3 antibodies, absent during pregnancy, were detected two months later, and whose child had severe thrombocytopenia with bruising [48].

Care of the newborn. The child of a mother with GT is considered at high bleeding risk, and severe neonatal bleeding is concentrated in the children of affected and immunised mothers [17]. In any newborn with suspected platelet dysfunction or at risk of neonatal thrombocytopenia, the PNDS contraindicates scalp electrodes and fetal scalp blood sampling, vacuum extraction and forceps, and recommends oral vitamin K, a full blood count and platelet studies on cord blood at birth, repeat platelet counts on days 3 and 5, compression for at least 10 minutes after any venepuncture and daily paediatric examination until discharge [17]. In severe thrombocytopenia, transfontanellar ultrasound is performed, which may be falsely reassuring, with computed tomography in case of doubt or suspected posterior fossa haemorrhage; suspected intracranial haemorrhage requires early platelets [17]. In FNAIT, the count continues to fall during the first days and recovers to haemostatic values (70 × 10⁹/L) in about ten days, with serial counts until normalisation and IVIg and/or platelets if thrombocytopenia is severe or there is serious bleeding [17].

Lactation. The US rFVIIa label has no information on passage into breast milk and recommends weighing the benefits of breastfeeding against maternal clinical need [19]. In pregnancy, animal studies with eptacog alfa showed no teratogenicity, and there are no controlled studies in pregnant women [19].

7.14. Surgery, procedures and anaesthesia

Planned surgery requires a multidisciplinary team (surgeon, anaesthetist, haematologist, pharmacist and blood service), a written protocol with haemostatic treatment and anaesthetic precautions, and a centre with 24-hour support and blood products; outpatient care is limited to procedures with minor bleeding risk, such as dental care, cataract surgery and minor skin surgery [10]. The French regimen provides for platelet concentrates one hour before and every 12–24 hours or, in refractoriness or platelet unavailability, rFVIIa 10 minutes before and every 2–3 hours, with intravenous or oral tranexamic acid and local haemostasis (fibrin glue, topical tranexamic acid) [10]. In Europe, 56% of centres maintain rFVIIa for at least one day after minor surgery and 67% for at least four days after major surgery, and 87% use the dose recommended in the SmPC [11]. In the GTR, the mean duration of rFVIIa in major surgery was slightly less than 3 days, without postoperative bleeding [11]. The 2020 PNDS adds: testing for anti-HLA and anti-αIIbβ3 antibodies at the preoperative consultation; platelets (one hour before) as first line in patients without immunisation or known refractoriness, and rFVIIa (immediately before the procedure) in alloimmunisation or isoimmunisation with refractoriness, within the terms of the marketing authorisation; first-line use of rFVIIa outside these terms discussed when there is immunisation without known refractoriness or when prevention of immunisation is essential (high-risk variant, obstetric future), with justification in the medical record; measurement of intraoperative losses; and cover for a few hours to 1–2 days for minor procedures and several days for major surgery or biopsies of deep organs (kidney, liver), with prolonged hospital stay [17].

Epidural and spinal anaesthesia, locoregional anaesthesia and intramuscular analgesics should be strictly avoided; in ophthalmic surgery, retrobulbar block is contraindicated and topical anaesthesia is used; central venous catheters (subclavian or femoral) should be avoided and, if necessary, inserted under ultrasound guidance after haemostatic correction [10]. Bone marrow donation is contraindicated, and post-mortem organ and tissue donation is possible after individual assessment [10].

The SPATA study of surgical procedures in 423 patients with inherited platelet disorders (829 procedures) found excessive bleeding in 19.7%; preoperative prohaemostatic treatment was associated with less bleeding in platelet function disorders, and predictors were a preoperative World Health Organization bleeding score ≥2, disease type, surgery type and female sex (cited by GeneGuidance) [53]. According to the EAHAD survey, in an analysis of 182 procedures in 89 patients with platelet disorders, inadequate transfusion was associated with more excessive bleeding, and in the SPATA-DVT study (210 procedures in 155 patients), none of the five patients with GT received thromboprophylaxis and two thromboembolic events (4.7%) occurred after high-risk procedures without prophylaxis [11]. In Europe, 62% of centres do not use pharmacological thromboprophylaxis for surgery in patients with GT [11]. The PNDS, by contrast, recommends prevention of venous thromboembolism in situations of increased risk due to the type of surgery or comorbidities, with early mobilisation, intermittent pneumatic compression and low-molecular-weight heparin at the usual prophylactic dose for as long as prohaemostatic treatment lasts, with case-by-case decisions thereafter; all unexpected events during the surgical episode are recorded in the medical record [17]. Pulmonary embolism two months after cervical discectomy in a patient who had received rFVIIa, platelets and tranexamic acid shows that GT does not protect against provoked venous thromboembolism and that the therapeutic window for anticoagulation is narrow: the patient was treated with apixaban, which was stopped at four months after a spontaneous haemarthrosis [32].

7.15. Haematopoietic stem cell transplantation

Allogeneic HSCT is the only established curative treatment and is reserved for selected patients with recurrent severe bleeding or antiplatelet antibodies and refractoriness [6, 33, 85]. At Great Ormond Street (London), five consecutive children underwent successful transplantation, three with reduced-intensity conditioning and unrelated donors, in the first report of this strategy in GT [85]. At the University of California, Los Angeles, two children received HSCT from unrelated donors (one from cord blood), with engraftment and normalisation of aggregation, but with several post-transplant complications [86]. In Detroit, two siblings underwent successful transplantation with mixed chimerism; the authors reviewed Center for International Blood and Marrow Transplant Research (CIBMTR) registry data from 2008–2022 and recommend monitoring platelet αIIb/β3 expression by flow cytometry to detect late rejection, particularly when anti-GPIIb/IIIa antibodies were present before transplantation [87]. Conditioning and immunosuppression frequently lead to disappearance of isoantibodies, but recipient antibodies may compromise engraftment [3, 77]. Reduced-intensity conditioning is associated with lower toxicity and a higher risk of rejection, including one case with 30% chimerism, whereas myeloablative conditioning, used in the case in section 10, achieves complete chimerism with greater toxicity [33]. There are no large comparative studies, and in Europe 89% of centres have no transplanted patients [11, 33]. In LAD-III, which may mimic GT, HSCT is the only curative treatment and should be performed early [50]. The PNDS recommends discussing allogeneic HSCT with a specialist multidisciplinary team in patients with a severe bleeding phenotype and episodes refractory to conventional treatment, and discussing the indication systematically and early in LAD-III [17].

7.16. Developments in the last 12 months and investigational therapies

Sutacimig is based on preclinical and ex vivo studies: TLT-1 (TREM-like transcript-1) is absent from resting platelets but is induced by activation, including in platelets from patients with GT; by concentrating endogenous FVIIa on the activated platelet, the antibody promotes local factor X activation and αIIbβ3-independent thrombin generation without interfering with the normal function of FVIIa, TLT-1 or aggregation; in 13 patients with GT, plasma FVII and FVIIa were normal, and dose- and time-dependent accumulation of endogenous FVIIa was observed in primates [44]. According to the company, the FDA granted Fast Track, orphan drug and Breakthrough Therapy designations for GT, the EMA granted orphan drug designation and access to the PRIME scheme, and the UK Medicines and Healthcare products Regulatory Agency (MHRA) granted access to the Innovative Licensing and Access Pathway (ILAP); the FDA considered the data sufficient for a phase 3 trial with 0.2 mg/kg subcutaneously once weekly, planned for the second half of 2026, with no registration identified on ClinicalTrials.gov by 10-10-2026 [21]. These designations do not constitute marketing authorisation, efficacy results have no published confidence intervals or absolute values, and the three grade 2 thromboembolic events, in higher-exposure cohorts or patients with several risk factors, require evaluation in the phase 3 trial [21, 89]. The programme extends to congenital factor VII deficiency, with a trial recruiting since March 2026 (NCT07347249) [94]. The GT trial inclusion criteria excluded combined oral contraceptives containing oestrogen [88]. A 2025 American Society of Hematology meeting abstract with the phase 2 analysis was cited in recent literature [39].

The search of ClinicalTrials.gov and Europe PMC did not identify human gene therapy trials in GT; that result does not prove their absence [27, 95]. Gene therapy models may stimulate production of isoantibodies against newly expressed αIIbβ3, and stable, safe expression in humans has not yet been achieved [3, 77]. Observational studies are registered: the Glanzmann Thrombasthenia Natural History Study+ (UMC Utrecht, NCT06204042; estimated 200 patients, ≥16 years), probably associated with the natural history study launched by the EAHAD GT working group, an American registry (ATHNdataset, NCT06820515), a study of experiences of living with GT (Haemnet, NCT05315232, completed) and a sublingual videomicroscopy study to predict bleeding (Lille, NCT04119908) [11, 95, 96]. The herbal haemostatic agent Ankaferd has only isolated reports, without robust evidence [42].

7.17. Agents to avoid, transition and special situations

Aspirin and NSAIDs, antiplatelet agents, anticoagulants (unless individually indicated after thromboembolism), intramuscular injections and neuraxial and locoregional anaesthesia should be avoided [3, 10]. Concomitant aPCC increases the thrombotic risk of rFVIIa [19]. The French PNDS describes transition in two dimensions: transition of care, in which the young person progressively takes over management of the disease (cognitive and emotional dimension), and transition of team, with the move from the paediatric to the adult setting (social and organisational dimension); it is a period in which adherence to treatment and follow-up tends to decline [17]. The critical milestones for which transition should prepare patients are menarche, contraceptive choice, reproductive planning and maintenance of antibody and transfusion records [3, 10, 30].

Infection prevention in LAD-III. The PNDS recommends measuring immunoglobulins in all patients with LAD-III and deciding with the centre on the indication, dose and frequency of replacement for any deficiency; discussing antibacterial and antifungal prophylaxis with the centre and infectious diseases; and, in the presence of fever, looking for a focus (particularly pulmonary and cutaneous), taking blood cultures and samples from any portal of entry, and immediately starting empirical broad-spectrum intravenous antibiotics active against Pseudomonas aeruginosa, then adjusted to the antibiogram, with an antifungal from the outset or in case of failure [17].

7.18. Guideline recommendations and differences

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

GT is inherited in an autosomal recessive manner [2, 3]. When both parents are heterozygous, each pregnancy has a 25% probability of an affected child, 50% of an asymptomatic carrier child and 25% of a child without the variant; an unaffected sibling of a patient has a two-thirds probability of being a carrier. Children of a person with GT are obligate asymptomatic heterozygotes if the other parent is not a carrier; if the partner is a carrier, which is more likely in consanguineous unions or within populations with a founder variant, the risk of an affected child is 50% [3, 10]. Double heterozygosity, with one variant in each gene, does not cause GT, so a couple in which each partner carries a variant in a different gene is not at risk of affected children [3]. The GeneReviews founder variant tables note that rare de novo variants may occur, which is relevant when only one parent carries the identified variant [14].

Allelic disorders have different risks: macrothrombocytopenia caused by activating ITGA2B or ITGB3 variants is autosomal dominant, with a 50% risk of transmission per pregnancy [12, 13]. FNAIT due to HPA-1a incompatibility depends on the maternal and paternal platelet genotypes rather than a disease in the carrier [7].

8.2. Cascade testing and carrier screening

Once both variants have been identified in the proband, targeted testing allows confirmation of phase in the parents, diagnosis of siblings with mild symptoms or no symptoms, and identification of carriers [3]. The French PNDS recommends, where possible, systematic laboratory phenotyping of relatives, at least first-degree relatives, whether symptomatic or not [17]. αIIbβ3 quantification by flow cytometry does not reliably identify carriers because values overlap with normal values [1]. Carrier screening in the partner of an affected person is recommended when there is consanguinity, but only 18% of European centres perform it routinely and 52% only in the presence of consanguinity [3, 30, 48]. The PNDS makes no general recommendation on screening the partner, which it considers justifiable in a context of strong family consanguinity [17]. In populations with a founder variant, targeted testing for that variant is efficient, but a negative result does not exclude another variant in the same gene [1, 3]. The strong actionability assigned by ClinGen in children supports diagnosing minor siblings at risk of disease, who benefit from preventive care and a haemostatic plan before procedures [6]. The sources consulted do not specifically address carrier testing in asymptomatic minors.

8.3. Prenatal diagnosis and preimplantation genetic testing

Prenatal diagnosis is performed by analysis of familial variants in chorionic villus DNA; fetal blood flow cytometry by cordocentesis has been abandoned because of the risk of bleeding and fetal loss [1]. PGT is an option when both familial variants are known and may be combined with in vitro fertilisation, which half of the published women with GT required to conceive [3, 48]. The same variant may cause highly variable severity, which should be explained in prenatal counselling [1]. In a pregnancy at risk of an affected fetus or FNAIT, caesarean section may be preferred to avoid instrumentation [48]. In France, prenatal diagnosis and preimplantation diagnosis are offered within the framework of the bioethics laws [17].

8.4. Counselling content

Counselling should address mode of transmission, variable severity without predictable genotype correlation, the risk of alloimmunisation associated with transfusions and pregnancies, reproductive implications for affected women (HMB, fertility, PPH, FNAIT), and the need to test the partner in consanguineous unions [3, 30, 48]. Interpretation of a heterozygous ITGA2B or ITGB3 variant depends on the platelet phenotype: carrier status with normal platelets or dominant disease with macrothrombocytopenia [7]. Bone marrow donation by people with GT is contraindicated [10]. The PNDS organises disclosure of the diagnosis in a consultation with the centre physician, ideally with the nurse, and with psychological support available; information (nature of the disease, risks in daily life, during invasive procedures and after trauma, course, transmission, prevention and treatment) and collection of consent for molecular testing are spread over successive consultations [17].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each number measures

The 2006 review considers it unwise to estimate worldwide prevalence because GT is concentrated in populations with high consanguinity [1]. In the George review (177 patients, 1990), only 12 were from the USA, compared with 55 from Israel and Jordan and 42 from southern India; 382 patients have been reported in Iran [1].

9.2. Founder and consanguineous populations

GT is relatively frequent among Hindus in southern India, Iraqi Jews, Arabs in Israel, Roma in France (Manouche) and nomadic tribes in Jordan [1]. In India, ITGB3 variants predominate, particularly in exon 4, and in the Mumbai series 73.4% of patients were born to consanguineous parents [1, 42]. Iraqi Jews share the ITGB3 c.2031_2041del deletion and Manouche Roma the ITGA2B c.1544+1G>A variant, both with a founder effect and accounting for virtually all pathogenic alleles described in those groups [14, 15]. In Tunisia, a nonsense variant is common [7]. LAD-III, the main phenocopy, also clusters in consanguineous populations in Turkey, Israel and the Arabian Peninsula [50]. In France, a homozygous ITGA2B variant was found exclusively in patients from the Traveller community (gens du voyage), a finding consistent with the founder effect described in Manouche Roma [15, 17].

9.3. USA and Europe

In the EPIC Cosmos cohort of 1059 American patients, 58.5% were female, with no sex differences in bleeding burden, and annualised mortality was higher than in the general population [16]. In Europe, published series include the Paris cohort (64 patients), the French prospective antibody study (55 patients), the Spanish RETPLAC registry (37 patients) and the Dutch survey (36 patients with GT followed) [1, 38, 39, 75]. In an Italian series, 17 of 21 variants were in ITGA2B [1]. In the European EAHAD survey, 48% of centres follow fewer than five patients and eight follow more than 20, including one in Portugal, the only Portuguese respondent [11]. The sources consulted do not include epidemiological data from Brazil.

9.4. Special populations

Women and girls are the population with the greatest burden: HMB in almost all, risk at menarche, infertility, PPH and pregnancy-related alloimmunisation [30, 48]. Children account for severe epistaxis and most treated bleeding in the GTR [3, 19]. In resource-limited countries, lack of access to rFVIIa and selected platelets and use of whole blood and plasma before diagnosis explain the mortality observed in India [42]. Data in people aged 65 years or older are insufficient in the rFVIIa label [19].

9.5. Reference networks and patient associations

The relevant European reference network is ERN-EuroBloodNet, for rare haematological diseases [25]. The EAHAD GT working group develops practice surveys and the natural history study [11, 26]. The World Federation of Hemophilia includes platelet disorders within its scope [97]. Glanzmann's Research Foundation is an American patient association dedicated to GT [98]. In France, the reference centre for inherited platelet disorders developed the emergency consensus with patient associations, and the French version is available in the Orphanet Urgences collection [10]. The Spanish RETPLAC registry, of the Grupo Español de Alteraciones Plaquetarias Congénitas (GEAPC) and Sociedad Española de Trombosis y Hemostasia (SETH), is listed in the European registry directory [39].

Organisation of care in France. Diagnosis and initial assessment take place at a specialist centre of the inherited bleeding disorders network (MHEMO filière): the Resource and Competence Centres for Inherited Bleeding Disorders (CRC-MHC) receive patients referred by the attending physician, and diagnostic confirmation is carried out at the Reference Centre for Inherited Platelet Disorders (CRPP), coordinated in Marseille (La Timone Hospital), with constituent sites in Bordeaux, Paris (Robert-Debré Hospital and Armand-Trousseau Hospital) and Toulouse and a network of competence centres across the country [17]. The centre physician issues the Ministry of Health care and emergency card, which states the disease, the most effective treatment and the team's permanent contact details and should be updated during follow-up [17]. GT and related platelet disorders are long-term conditions (ALD) exempt from patient co-payment (ticket modérateur); the first application may be made by the specialist up to the age of 16 and thereafter by the attending physician [17]. At school, entry should not be delayed, and an individualised reception plan (PAI), validated by the family, the head teacher, the physician of the host institution and the centre physician, defines what to do in case of bleeding or trauma and the adaptations of high-risk physical activities or for girls with anaemia [17]. The Association Française des Hémophiles (AFH), with a Platelet Disorders Committee, supports patients and families in all regions and contributes to therapeutic education [17].

10. Illustrative Clinical Case

Li and colleagues described in 2021 a 32-month-old boy, followed at West China Second Hospital (Sichuan, China), with recurrent mucocutaneous bleeding from birth [33]. His parents were consanguineous, and a sister and a brother had died at 3 years of age from severe bleeding, in both cases epistaxis. At 29 months, he was admitted for monthly epistaxis lasting 3 to 8 days, refractory to local measures and haemostatic agents, which had required four platelet transfusions and one red cell transfusion. Platelet count and morphology and coagulation tests were normal, allowing exclusion of immune thrombocytopenia, haemophilia and leukaemia. Flow cytometry showed reduced CD61 (32.4%) and CD41a (56.2%) expression, and maximum aggregation was 16.6% with ADP (normal 50–100%) and 29.9% with arachidonic acid (normal 60–100%) [33].

Sequencing identified in homozygosity the ITGB3 variant described by the authors as “exon9:c.1199G>A”, without specifying the transcript; the parents were heterozygous, as shown by the electropherograms in Figure 1 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8859262/figure/F1/) [33]. Normalised in VariantValidator against the MANE Select transcript, the variant corresponds to NM_000212.3(ITGB3):c.1199G>A, NP_000203.2:p.(Cys400Tyr), NC_000017.11:g.47291027G>A, known in historical nomenclature, counted from the mature protein, as C374Y; ClinVar classifies it as pathogenic, by a ClinGen expert panel, for GT (VCV 13562) [34, 35]. The authors classified the disease as a variant form (“type III”), based on receptor expression above 20% with defective function [33].

In view of recurrent potentially fatal bleeding, a family history of two deaths and transfusion dependence, the team chose peripheral blood HSCT from his 9-year-old sister, an asymptomatic heterozygote and HLA-identical donor, performed on 13 March 2020, with busulfan- and cyclophosphamide-based myeloablative conditioning, a dose of 6.0×10⁶ CD34+ cells/kg and graft-versus-host disease (GVHD) prophylaxis with ciclosporin and short-course methotrexate [33]. Neutrophil and platelet engraftment occurred on day +11 and donor chimerism was complete on day +20; on day +25, CD61 expression was 84.6% and CD41a expression was 85.3%, as shown in Figure 2 of the article (https://pmc.ncbi.nlm.nih.gov/articles/PMC8859262/figure/F2/) [33]. Epstein–Barr viraemia (6.35×10⁵ copies/mL), one month after transplantation, resolved within two weeks with aciclovir; there was no GVHD, ciclosporin was withdrawn at 6 months and, at 20 months of follow-up, the patient had experienced no further bleeding [33].

The case brings together several elements of this article: consanguinity and childhood sibling deaths as warning signs, epistaxis as the main cause of severe bleeding in children, the variant form with partial receptor expression, and the role of HSCT as the only curative treatment [3, 33]. HSCT with myeloablative conditioning from an HLA-identical family donor is not routine management in GT: reference sources reserve it for selected patients with recurrent severe bleeding or platelet refractoriness, and several series used reduced-intensity conditioning to reduce toxicity [3, 85]. Conditioning agent doses should not be extrapolated from the report.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

With organised supportive care at a haemostasis centre, the survival prognosis of diagnosed patients is good, and severity tends to decrease with age, except for menstrual and obstetric bleeding [1, 3, 7]. Prognosis depends mainly on three factors: access to haemostatic treatment (in the Indian study, 12 of the 13 bleeding deaths were attributed to treatment unavailability), development of alloimmunisation and refractoriness, which reduces treatment options, and, in women, management of menarche, fertility and childbirth [42, 46, 48]. In the American cohort, anaemia (35.6%) and transfusion dependence (16.4%) were frequent, and annualised mortality exceeded that of the general population [16]. The annualised bleeding rate varies widely between settings: a mean of 11.85 in Mumbai, a median of 3 among Spanish patients starting prophylaxis [39, 42]. After successful HSCT, correction is durable, but mixed chimerism and late rejection require surveillance [33, 87]. The French PNDS estimates a near-normal life expectancy, in contrast with the mortality above that of the general population in the American cohort based on diagnostic codes; it considers ischaemic cardiovascular risk probably lower than in the general population, but not zero, so cardiovascular risk factors should be prevented and treated [16, 17].

11.2. Surveillance

11.3. Long-term follow-up

Follow-up combines patient and family education (emergency card, avoidance of NSAIDs and intramuscular injections, local measures and tranexamic acid at home), transfusion and antibody records, and advance preparation for each procedure [3, 10]. Inclusion in registries and use of standardised instruments (ISTH-BAT, PBAC, EQ-5D) allow monitoring of bleeding burden, although their suitability in GT is limited [11]. The EAHAD and UMC Utrecht natural history study aims to estimate bleeding burden using prospective data [11, 96]. Therapeutic education, started early and adapted to age, is directed at the patient and caregivers, starts from an educational diagnosis and addresses management of risk situations (epistaxis, gingival bleeding, HMB, internal bleeding), transmission and understanding of the disease, in individual or group sessions with a multidisciplinary team that may include an expert patient and materials adapted to the level of literacy [17]. Follow-up also aims to prevent school, social and occupational isolation, keep the care and emergency card up to date and share important documents in the shared medical record [17].

12. Summary and Final Considerations

Glanzmann thrombasthenia is an autosomal recessive platelet disorder caused by biallelic ITGA2B or ITGB3 variants, which eliminate or inactivate integrin αIIbβ3 and prevent platelet aggregation. Its most characteristic feature is the combination of mucocutaneous bleeding, often from birth, with normal platelet count and morphology, normal coagulation tests and absent aggregation to all agonists except ristocetin. Diagnosis follows the sequence of light transmission aggregometry, CD41/CD61 flow cytometry (with activation testing in variant forms) and sequencing of both genes, with deletion analysis when one variant is missing; LAD-III, RASGRP2-related platelet dysfunction and the acquired autoantibody-mediated form are the main phenocopies. The same gene family also causes dominant macrothrombocytopenia through activating variants, requiring each heterozygous variant to be interpreted in light of platelet size and count.

Severity does not track the amount of residual receptor. Epistaxis dominates childhood, menstrual and obstetric bleeding dominate women's lives, and iron deficiency is frequent. Treatment rests on local measures and tranexamic acid, platelets, preferably HLA-matched, in patients without refractoriness, and eptacog alfa (activated) in refractory patients or when platelets are unavailable; the European indication is broader than the American indication, and early use to avoid alloimmunisation is frequent practice but off-label. Anti-αIIbβ3 and anti-HLA alloimmunisation, more frequent in type I with null variants such as the Manouche variant, affects transfusions, pregnancies and transplants and warrants antibody monitoring. Pregnancy requires multidisciplinary planning, antibody surveillance and prolonged haemostatic cover because of the frequency of postpartum haemorrhage and the risk of neonatal alloimmune thrombocytopenia. HSCT remains the only curative treatment, for selected severe cases. Sutacimig, a subcutaneous bispecific antibody with FDA breakthrough therapy designation, awaits a phase 3 trial, and gene therapy remains preclinical. There is no specific international therapeutic guideline, and much of practice rests on observational registries, expert consensus and surveys.

13. Bibliographic References

1. Nurden AT. Glanzmann thrombasthenia. Orphanet J Rare Dis. 2006;1:10. doi:10.1186/1750-1172-1-10
2. Orphanet. Glanzmann thrombasthenia (ORPHA:849) [Internet]. Paris: INSERM; [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/849
3. Botero JP, Lee K, Branchford BR, Bray PF, Freson K, Lambert MP, et al.; ClinGen Platelet Disorder Variant Curation Expert Panel. Glanzmann thrombasthenia: genetic basis and clinical correlates. Haematologica. 2020;105(4):888-894. doi:10.3324/haematol.2018.214239
4. MedGen. Glanzmann thrombasthenia 1 (CN300358; OMIM 273800). Bethesda: NCBI. Available from: https://www.ncbi.nlm.nih.gov/medgen/981753
5. MedGen. Glanzmann thrombasthenia 2 (C5543273; OMIM 619267). Available from: https://www.ncbi.nlm.nih.gov/medgen/1782592
6. GeneGuidance. ITGA2B — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-10.
7. GeneGuidance. ITGB3 — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-10.
8. VariantValidator. NM_000419.5:c.1544+1G>A (GRCh38, MANE Select) [Internet]. Manchester: University of Manchester; [cited 2026-10-10]. Available from: https://variantvalidator.org
9. VariantValidator. NM_000212.3:c.2031_2041del (GRCh38, MANE Select) [Internet]. Manchester: University of Manchester; [cited 2026-10-10]. Available from: https://variantvalidator.org
10. Fiore M, Giraudet JS, Alessi MC, Falaise C, Desprez D, d'Oiron R, et al. Emergency management of patients with Glanzmann thrombasthenia: consensus recommendations from the French reference center for inherited platelet disorders. Orphanet J Rare Dis. 2023;18(1):171. doi:10.1186/s13023-023-02787-2
11. Fiore M, Artoni A, Klamroth R, Mathias M, Schutgens R, d'Oiron R, et al. European Management of Glanzmann's Thrombasthenia: A Survey of Current Clinical Practice. Haemophilia. 2025;31(6):1261-1270. doi:10.1111/hae.70114
12. MedGen. Bleeding disorder, platelet-type, 16 (C5442010; OMIM 187800). Available from: https://www.ncbi.nlm.nih.gov/medgen/1781222
13. MedGen. Bleeding disorder, platelet-type, 24 (C5543280; OMIM 619271). Available from: https://www.ncbi.nlm.nih.gov/medgen/1785711
14. GeneReviews® Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Sephardic Jewish Population. 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/NBK1116/
15. GeneReviews® Resources for Genetics Professionals — Genetic Disorders Associated with Founder Variants Common in the Romani Population. 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/NBK1116/
16. Citla-Sridhar D, Liu D. Characterising Glanzmann Thrombasthenia in the United States: Real-World Data From the EPIC Cosmos Dataset. Haemophilia. 2026;32(1):155-165. doi:10.1111/hae.70170
17. Haute Autorité de Santé. Protocole National de Diagnostic et de Soins (PNDS): Thrombasthénie de Glanzmann et pathologies plaquettaires apparentées. Saint-Denis La Plaine: HAS; 2020 [text dated December 2019, Centre de Référence des Pathologies Plaquettaires Constitutionnelles; published 2020-01-27; cited 2026-11-06]. Available from: https://www.has-sante.fr/jcms/p_3147545
18. Gresele P; Subcommittee on Platelet Physiology of the International Society on Thrombosis and Hemostasis. Diagnosis of inherited platelet function disorders: guidance from the SSC of the ISTH. J Thromb Haemost. 2015;13(2):314-322. doi:10.1111/jth.12792
19. 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
20. European Medicines Agency. NovoSeven (eptacog alfa [activated]): EPAR — product information [Internet]. Amsterdam: EMA; updated 2023-02-27 [cited 2026-10-10]. Available from: https://www.ema.europa.eu/en/medicines/human/EPAR/novoseven
21. Hemab Therapeutics. Hemab Therapeutics reports second quarter 2026 financial results and provides corporate update. Form 8-K, Exhibit 99.1. 2026 Aug 11. Available from: https://sec.gov/Archives/edgar/data/2114044/000119312526343421/d180684dex991.htm
22. Harrison P, Mackie I, Mumford A, Briggs C, Liesner R, Winter M, et al.; British Committee for Standards in Haematology. Guidelines for the laboratory investigation of heritable disorders of platelet function. Br J Haematol. 2011;155(1):30-44. doi:10.1111/j.1365-2141.2011.08793.x
23. Bolton-Maggs PH, Chalmers EA, Collins PW, Harrison P, Kitchen S, Liesner RJ, et al.; UKHCDO. A review of inherited platelet disorders with guidelines for their management on behalf of the UKHCDO. Br J Haematol. 2006;135(5):603-633. doi:10.1111/j.1365-2141.2006.06343.x
24. Gebetsberger J, Knöfler R, Streif W; ThromKidplus study group. "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
25. European Reference Network on Rare Hematological Diseases (ERN-EuroBloodNet) [Internet]. [cited 2026-10-10]. Available from: https://eurobloodnet.eu/
26. European Association for Haemophilia and Allied Disorders (EAHAD) [Internet]. [cited 2026-10-10]. Available from: https://eahad.org/
27. Nurden AT, Nurden P. Glanzmann Thrombasthenia 10 Years Later: Progress Made and Future Directions. Semin Thromb Hemost. 2025;51(2):196-208. doi:10.1055/s-0044-1782519
28. Poon MC, Di Minno G, d'Oiron R, Zotz R. New Insights Into the Treatment of Glanzmann Thrombasthenia. Transfus Med Rev. 2016;30(2):92-99. doi:10.1016/j.tmrv.2016.01.001
29. Di Minno G, Zotz RB, d'Oiron R, Bindslev N, Di Minno MN, Poon MC, et al. The international, prospective Glanzmann Thrombasthenia Registry: treatment modalities and outcomes of non-surgical bleeding episodes in patients with Glanzmann thrombasthenia. Haematologica. 2015;100(8):1031-1037. doi:10.3324/haematol.2014.121475
30. Rutten KHG, Schutgens REG, d'Oiron R, Fiore M, Castaman G, Gomez K, et al. International Practices in Managing Preconception, Pregnancy and Childbirth in Women With Glanzmann Thrombasthenia: A Survey From the European Association of Haemophilia and Allied Disorders (EAHAD). Haemophilia. 2026;32(2):554-560. doi:10.1111/hae.70186
31. Konkle BA, Nakaya Fletcher S. Hemophilia A. 2000 Sep 21 [updated 2025 Aug 7]. 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/NBK1404/
32. Mohammad Alizade T, Karimi R, Kazemizadeh H, Khoshnam Rad N. Pulmonary thromboembolism in Glanzmann Thrombasthenia: a case report and systematic literature review. Ann Hematol. 2026;105(2):64. doi:10.1007/s00277-026-06732-8
33. Li JH, Sun SW, Ai Y, Yang X, Zhu YP. Excellent Outcome Following Sibling Peripheral Blood Hematopoietic Stem Cell Transplantation for Glanzmann Thrombasthenia: A Case Report. Front Pediatr. 2021;9:776927. doi:10.3389/fped.2021.776927
34. VariantValidator. NM_000212.3:c.1199G>A (GRCh38, MANE Select) [Internet]. Manchester: University of Manchester; [cited 2026-10-10]. Available from: https://variantvalidator.org
35. ClinVar. VCV000013562 — NM_000212.3(ITGB3):c.1199G>A (p.Cys400Tyr). Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/13562/
36. ClinVar. VCV001691479 — NM_000212.3(ITGB3):c.2031_2041del (p.Asp677fs). Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/1691479/
37. ClinVar. VCV000002895 — NM_000419.5(ITGA2B):c.1544+1G>A. Available from: https://www.ncbi.nlm.nih.gov/clinvar/variation/2895/
38. Desprez D, d'Oiron R, Voisin S, Falaise C, Alessi MC, Saultier P, et al. Natural history of antiplatelet antibody formation in patients with Glanzmann thrombasthenia: a French multicenter prospective study. J Thromb Haemost. 2026;24(7):2627-2639. doi:10.1016/j.jtha.2026.03.024
39. García-Jaén P, Fernández-Mosteirin N, Serrano ML, Riesco S, Aguilar C, Gabaldon D, et al. Efficacy and safety of recombinant activated factor VII for secondary prophylaxis in patients with Glanzmann thrombasthenia. Res Pract Thromb Haemost. 2026;10(4):106792. doi:10.1016/j.rpth.2026.106792
40. Orphanet. Autosomal dominant macrothrombocytopenia (ORPHA:140957) [Internet]. [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/140957
41. Konkle BA, Nakaya Fletcher S. Hemophilia B. 2000 Oct 2 [updated 2025 Aug 7]. 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/NBK1495/
42. 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
43. Saultier P, Grino M, Falaise C, Voisin S, Lavenu-Bombled C, Ibrahim-Kosta M, et al. Efficacy and safety of recombinant activated factor VII in Glanzmann thrombasthenia: A systematic literature review. Haemophilia. 2025;31(1):7-15. doi:10.1111/hae.15130
44. Gandhi PS, Zivkovic M, Østergaard H, Bonde AC, Elm T, Løvgreen MN, et al. A bispecific antibody approach for the potential prophylactic treatment of inherited bleeding disorders. Nat Cardiovasc Res. 2024;3(2):166-185. doi:10.1038/s44161-023-00418-4
45. Tiwari SK, Sonowal R, Bhowmick R, Joshi P. Management of Severe Menorrhagia in an Adolescent with Glanzmann Thrombasthenia: A Case Report and Treatment Approach. J Pediatr Adolesc Gynecol. 2026;39(2):253-257. doi:10.1016/j.jpag.2025.11.008
46. Fiore M, d'Oiron R, Pillois X, Alessi MC. Anti-αIIbβ3 immunization in Glanzmann thrombasthenia: review of literature and treatment recommendations. Br J Haematol. 2018;181(2):173-182. doi:10.1111/bjh.15087
47. Savoia A, Pecci A. MYH9-Related Disease. 2008 Nov 20 [updated 2021 Feb 18]. 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/NBK2689/
48. Rutten KHG, Tsiamita O, Van Thillo Q, Raheja P, Kaler M, van Galen KPM, et al. Management of pregnancy and childbirth in Glanzmann thrombasthenia: A case series and review. Br J Haematol. 2025;207(4):1702-1708. doi:10.1111/bjh.70056
49. Cattaneo M, Cerletti C, Harrison P, Hayward CP, Kenny D, Nugent D, et al. Recommendations for the standardization of light transmission aggregometry: a consensus of the working party from the platelet physiology subcommittee of SSC/ISTH. J Thromb Haemost. 2013 Apr 10 [Epub ahead of print]. doi:10.1111/jth.12231
50. GeneGuidance. FERMT3 — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-10.
51. Spranger JW, Brill PW, Hall C, Nishimura G, Superti-Furga A, Unger S. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 4th ed. Oxford University Press; 2018. p. 575.
52. GeneGuidance. GP1BA — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-10.
53. GeneGuidance. NBEAL2 — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-10.
54. Orphanet. Gray platelet syndrome (ORPHA:721) [Internet]. [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/721
55. Introne WJ, Huizing M, Malicdan MCV, O'Brien KJ, Gahl WA. Hermansky-Pudlak Syndrome. 2000 Jul 24 [updated 2023 Mar 16]. 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/NBK1287/
56. Deuitch N, Broadbridge E, Cunningham L, Liu P. RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies. 2021 Mar 4 [revised 2025 Dec 4]. 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/NBK568319/
57. Orphanet. Familial platelet disorder with associated myeloid malignancy (ORPHA:71290) [Internet]. [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/71290
58. Perez Botero J, Dugan SN. ANKRD26-Related Thrombocytopenia. 2018 Jun 21 [updated 2026 Sep 15]. 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/NBK507664/
59. Pencheva B, Di Paola J, Porter CC. ETV6-Related Thrombocytopenia and Predisposition to Leukemia. 2020 Nov 19 [updated 2025 Jun 26]. 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/NBK564234/
60. Firth HV, Hurst JA. Oxford Desk Reference: Clinical Genetics and Genomics. 2nd ed. Oxford: Oxford University Press; 2017. p. 466–469.
61. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 42, section 42.5.1 Cytosolic Phospholipase A2α Deficiency.
62. Nyhan WL, Hoffmann GF, Al-Aqeel AI, Barshop BA. Atlas of Inherited Metabolic Diseases. 4th ed. Boca Raton: CRC Press; 2020. p. 439–448.
63. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 5, section 5.1.2 Glycogen Storage Disease Type I.
64. Orphanet. Leukocyte adhesion deficiency type III (ORPHA:99844) [Internet]. [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/99844
65. Orphanet. Bernard-Soulier syndrome (ORPHA:274) [Internet]. [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/274
66. Orphanet. MYH9-related syndromic thrombocytopenia (ORPHA:182050) [Internet]. [cited 2026-10-10]. Available from: https://www.orpha.net/en/disease/detail/182050
67. Heiman M, Gupta S, Lewandowska M, Shapiro AD. Complete Plasminogen Activator Inhibitor 1 Deficiency. 2017 Aug 3 [updated 2023 Feb 23]. 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/NBK447152/
68. Saudubray JM, Baumgartner MR, García-Cazorla Á, Walter J, editors. Inborn Metabolic Diseases: Diagnosis and Treatment. 7th ed. Berlin: Springer; 2022. Chapter 44, section 44.1.3 Other Types of Cellular Trafficking (Table 44.2).
69. GeneGuidance. RUNX1 — gene record (version dated 2026-09-26). Local project database; accessed on 2026-10-10.
70. King LJ, Huff J, Heber D, Miller MA, Marshall B. Management of Refractory Menstrual Bleeding in an Adolescent with Glanzmann Thrombasthenia: A Case Report and Review. Case Rep Obstet Gynecol. 2020;2020:8848763. doi:10.1155/2020/8848763
71. Ferring. DDAVP Injection (desmopressin acetate) prescribing information. DailyMed setid 651f6fee-a2c7-431b-8d5d-58b156c72244; current label 2022-09-28. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=651f6fee-a2c7-431b-8d5d-58b156c72244
72. INFARMED. Ddavp Desmopressin 0,004 mg/1 ml solução injetável (Ferring): Resumo das Características do Medicamento [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
73. Agence nationale de sécurité du médicament et des produits de santé. MINIRIN 4 microgrammes/mL, solution injectable (desmopressine): résumé des caractéristiques du produit, rubriques 4.1–4.3 [updated 2026 May 21; accessed 2026 Nov 7]. Base de données publique des médicaments. Available from: https://base-donnees-publique.medicaments.gouv.fr/medicament/67576220/extrait
74. Novo Nordisk Limited. NovoSeven — Summary of Product Characteristics (UK, PLGB 04668/0393), revision dated 2023-06-02. electronic medicines compendium [Internet]. Available from: https://www.medicines.org.uk/emc (search "NovoSeven")
75. 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
76. Poon MC, d'Oiron R, Baby S, Zotz RB, Di Minno G. The Glanzmann Thrombasthenia Registry: safety of platelet therapy in patients with Glanzmann thrombasthenia and changes in alloimmunization status. Haematologica. 2023;108(10):2855-2858. doi:10.3324/haematol.2022.281973
77. Nurden AT. Acquired Antibodies to αIIbβ3 in Glanzmann Thrombasthenia: From Transfusion and Pregnancy to Bone Marrow Transplants and Beyond. Transfus Med Rev. 2018 [Epub ahead of print, S0887-7963(18)30037-3]. doi:10.1016/j.tmrv.2018.05.002
78. AlNajjar M, Rochat R, Grimes AB, Navaei A, Eagar T, Martinez C, et al. Imlifidase Utilization in Glanzmann Thrombasthenia With Anti-GPIIb/IIIa and Anti-HLA Alloimmunization and Severe Platelet Refractoriness Following Hematopoietic Stem Cell Transplant. Pediatr Blood Cancer. 2025;72(3):e31412. doi:10.1002/pbc.31412
79. ClinicalTrials.gov. NCT04595617 — TAAS: Anti-αIIbβ3 immunization in Glanzmann thrombasthenia. Available from: https://clinicaltrials.gov/study/NCT04595617
80. Zotz RB, Poon MC, Di Minno G, d'Oiron R; Glanzmann Thrombasthenia Registry Investigators. The International Prospective Glanzmann Thrombasthenia Registry: Pediatric Treatment and Outcomes. TH Open. 2019;3(3):e286-e294. doi:10.1055/s-0039-1696657
81. Poon MC, d'Oiron R, Zotz RB, Bindslev N, Di Minno MN, Di Minno G, et al. The international, prospective Glanzmann Thrombasthenia Registry: treatment and outcomes in surgical intervention. Haematologica. 2015;100(8):1038-1044. doi:10.3324/haematol.2014.121384
82. National Hemophilia Foundation. FDA approves NovoSeven® RT for Glanzmann's thrombasthenia [Internet]. 2014 Jul. Available from: https://www.bleeding.org/news/fda-approves-novosevenr-rt-for-glanzmanns-thrombasthenia
83. Managed Healthcare Executive. FDA approves NovoSeven RT for Glanzmann's thrombasthenia [Internet]. 2014 Jul 11. Available from: https://www.managedhealthcareexecutive.com/view/fda-approves-novoseven-rt-glanzmanns-thrombasthenia
84. ClinicalTrials.gov. NCT04548791 — Marzeptacog alfa (activated) in inherited bleeding disorders. Available from: https://clinicaltrials.gov/study/NCT04548791
85. Connor P, Khair K, Liesner R, Amrolia P, Veys P, Ancliff P, et al. Stem cell transplantation for children with Glanzmann thrombasthenia. Br J Haematol. 2008;140(5):568-571. doi:10.1111/j.1365-2141.2007.06890.x
86. Friend BD, Roach GD, Kempert PH, Moore TB. Successful Use of Hematopoietic Stem Cell Transplantation for 2 Pediatric Cases of Glanzmann Thrombasthenia and Review of the Literature. J Pediatr Hematol Oncol. 2020;42(6):e521-e526. doi:10.1097/MPH.0000000000001646
87. Al-Antary ET, Chitlur M, Gadgeel M, Savaşan S. Mixed Chimerism and Clinical Outcome of Hematopoietic Stem Cell Transplantation in Glanzmann Thrombasthenia: Experience on 2 Siblings and Literature Review. J Pediatr Hematol Oncol. 2025;47(8):429-435. doi:10.1097/MPH.0000000000003121
88. ClinicalTrials.gov. NCT06211634 — A Phase 1/2 Study ... HMB-001 in Glanzmann thrombasthenia. Available from: https://clinicaltrials.gov/study/NCT06211634
89. Hemab Therapeutics. Hemab Therapeutics presents clinical and preclinical data from sutacimig in Glanzmann thrombasthenia and factor VII deficiency at the ISTH 2026 Congress [press release]. 2026 Jul 14. Available from: https://www.biospace.com/press-releases/hemab-therapeutics-presents-clinical-and-preclinical-data-from-sutacimig-in-glanzmann-thrombasthenia-and-factor-vii-deficiency-at-the-isth-2026-congress
90. ClinicalTrials.gov. NCT07136857 — STRENGTH: Eptacog beta in Glanzmann thrombasthenia. Available from: https://clinicaltrials.gov/study/NCT07136857
91. ClinicalTrials.gov. NCT06234813 — Concizumab in Glanzmann thrombasthenia: in vitro study. Available from: https://clinicaltrials.gov/study/NCT06234813
92. Dubut J, Goin V, Derray C, Huguenin Y, Fiore M. Targeting tissue factor pathway inhibitor with concizumab to improve hemostasis in patients with Glanzmann thrombasthenia: an in vitro study. J Thromb Haemost. 2024;22(9):2589-2600. doi:10.1016/j.jtha.2024.05.033
93. Sullivan SK, Mills JA, Koukouritaki SB, Vo KK, Lyde RB, Paluru P, et al. High-level transgene expression in induced pluripotent stem cell-derived megakaryocytes: correction of Glanzmann thrombasthenia. Blood. 2014;123(5):753-757. doi:10.1182/blood-2013-10-530725
94. ClinicalTrials.gov. NCT07347249 — Sutacimig in congenital factor VII deficiency. Available from: https://clinicaltrials.gov/study/NCT07347249
95. ClinicalTrials.gov. Search by condition “Glanzmann” (API v2) [Internet]. Bethesda: National Library of Medicine; [cited 2026-10-10]. Available from: https://clinicaltrials.gov/search?cond=Glanzmann
96. ClinicalTrials.gov. NCT06204042 — Glanzmann Thrombasthenia Natural History Study+. Available from: https://clinicaltrials.gov/study/NCT06204042
97. World Federation of Hemophilia [Internet]. Montreal: WFH; [cited 2026-10-10]. Available from: https://www.wfh.org/
98. Glanzmann's Research Foundation [Internet]. [cited 2026-10-10]. Available from: https://www.glanzmanns.org/