Hubbry Logo
Glanzmann's thrombastheniaGlanzmann's thrombastheniaMain
Open search
Glanzmann's thrombasthenia
Community hub
Glanzmann's thrombasthenia
logo
8 pages, 0 posts
0 subscribers
Be the first to start a discussion here.
Be the first to start a discussion here.
Glanzmann's thrombasthenia
Glanzmann's thrombasthenia
Glanzmann's thrombasthenia
View on Wikipedia
from Wikipedia
Glanzmann's thrombasthenia
Other namesThrombasthenia of Glanzmann and Naegeli[1]
This condition is inherited in a autosomal recessive manner.
SpecialtyHematology Edit this on Wikidata

Glanzmann's thrombasthenia is an abnormality of the platelets.[2] It is an extremely rare coagulopathy (bleeding disorder due to a blood abnormality), in which the platelets contain defective or low levels of glycoprotein IIb/IIIa (GpIIb/IIIa), which is a receptor for fibrinogen. As a result, no fibrinogen bridging of platelets to other platelets can occur, and the bleeding time is significantly prolonged.

Signs and symptoms

[edit]

Characteristically, there is increased mucosal bleeding:[3]

The bleeding tendency is variable but may be severe. Bleeding into the joints, particularly spontaneous bleeds, are very rare, in contrast to the hemophilias. Platelet numbers and morphology are normal. Platelet aggregation is normal with ristocetin, but impaired with other agonists such as ADP, thrombin, collagen, or epinephrine.[citation needed]

Cause

[edit]

Glanzmann's thrombasthenia can be inherited in an autosomal recessive manner[3][4] or acquired as an autoimmune disorder.[3][5]

The bleeding tendency in Glanzmann's thrombasthenia is variable,[3] some individuals having minimal bruising, while others have frequent, severe, potentially fatal hemorrhages. Moreover, platelet αIIbβ3 levels correlate poorly with hemorrhagic severity, as virtually undetectable αIIbβ3 levels can correlate with negligible bleeding symptoms, and 10–15% levels can correlate with severe bleeding.[6] Unidentified factors other than the platelet defect itself may have important roles.[3]

Pathophysiology

[edit]

Glanzmann's thrombasthenia is associated with abnormal integrin αIIbβ3, formerly known as glycoprotein IIb/IIIa (GpIIb/IIIa),[7] which is an integrin aggregation receptor on platelets. This receptor is activated when the platelet is stimulated by ADP, epinephrine, collagen, or thrombin. GpIIb/IIIa is essential to blood coagulation since the activated receptor has the ability to bind fibrinogen (as well as von Willebrand factor, fibronectin, and vitronectin), which is required for fibrinogen-dependent platelet-platelet interaction (aggregation).[citation needed] Understanding of the role of GpIIb/IIIa in Glanzmann's thrombasthenia led to the development of GpIIb/IIIa inhibitors, a class of powerful antiplatelet agents.[4][8]

Diagnosis

[edit]

Light transmission aggregometry is widely accepted as the gold standard diagnostic tool for assessing platelet function, and a result of absent aggregation with any agonist except ristocetin is highly specific for Glanzmann's thrombasthenia.[9] Following is a table comparing its result with other platelet aggregation disorders:

Platelet aggregation function by main disorders and agonists   edit
Further information: Platelet § Tests of function
ADP Epinephrine Collagen Ristocetin
P2Y receptor inhibitor or defect[10] Decreased Normal Normal Normal
Adrenergic receptor defect[10] Normal Decreased Normal Normal
Collagen receptor defect[10] Normal Normal Decreased or absent Normal
Normal Normal Normal Decreased or absent
Decreased Decreased Decreased Normal or decreased

Treatment

[edit]

Therapy involves both preventive measures and treatment of specific bleeding episodes.[3]

Eponym

[edit]

It is named after Eduard Glanzmann (1887–1959), the Swiss pediatrician who originally described it.[12][13][14]

History

[edit]

The subsequent studies, following Eduard Glanzmann's description of hemorrhagic symptoms and "weak platelets", demonstrated that these patients have prolonged bleeding times and their platelets failed to aggregate in response to activation. In the mid-1970s, Nurden and Caen[15] and Phillips and colleagues[16] discovered that thrombasthenic platelets are deficient in integrins αIIbβ3.

See also

[edit]

References

[edit]
[edit]
Revisions and contributorsEdit on WikipediaRead on Wikipedia

Glanzmann's thrombasthenia

View on Grokipedia
from Grokipedia
Glanzmann's thrombasthenia (GT) is a rare, congenital bleeding disorder characterized by impaired platelet aggregation due to quantitative or qualitative defects in the αIIbβ3 (also known as ), a key receptor on platelet surfaces essential for fibrinogen binding and clot formation. This autosomal recessive condition arises from mutations in the ITGA2B or ITGB3 genes on chromosome 17q21, resulting in deficient or dysfunctional expression that prevents normal despite normal platelet count and morphology. Affected individuals typically present with mucocutaneous bleeding starting from birth or , including frequent epistaxis, gingival bleeding, easy bruising, petechiae, and prolonged bleeding after minor trauma or procedures. In females, menorrhagia is common and can lead to , while about 25% of patients experience ; rarer complications include or hemarthrosis. Bleeding severity varies and often diminishes with age, though it can be exacerbated during , , or . GT has a global prevalence of approximately 1 in , though it is more frequent in populations with high , such as certain Iraqi Jewish, Arab, or South Asian communities, and reaches 1 in 200,000 in some regions. It is classified into three types based on residual levels: Type I (less than 5% expression, most severe), Type II (5-20% expression), and variant type (normal levels but with dysfunctional ). An acquired form exists rarely, triggered by autoantibodies against the in conditions like autoimmune disorders or malignancies. Diagnosis relies on clinical history of , normal platelet count, and specific tests such as light transmission platelet aggregometry (which shows absent aggregation to agonists like ADP or except ristocetin), flow cytometry to quantify expression, and genetic sequencing of ITGA2B and ITGB3. focuses on preventing and controlling episodes, with local measures and like for mild cases, platelet transfusions or recombinant activated factor VII for severe bleeds, as a potential cure in young patients, and emerging therapies including bispecific antibodies in clinical trials (as of 2025). Multidisciplinary care, including for carriers, is essential given the lifelong risk of hemorrhage.

Clinical Features

Signs and Symptoms

Glanzmann's thrombasthenia is characterized by a range of mucocutaneous manifestations due to impaired platelet function. Common primary symptoms include easy bruising manifesting as ecchymoses, petechiae on the skin, recurrent epistaxis often lasting more than 10 minutes, gingival during routine or dental procedures, and prolonged following minor cuts or trauma. In females, menorrhagia typically begins at and can be heavy and prolonged. These symptoms arise from defective platelet aggregation, leading to inadequate primary at sites of vascular injury. Symptoms usually become evident from infancy or , with many patients experiencing their first episode within the first year of . Initial presentations may include at birth, though this is less common. episodes are typically spontaneous or triggered by minor trauma and predominantly affect superficial mucocutaneous sites, sparing deeper tissues; unlike in hemophilia, hemarthroses and intramuscular hematomas are rare. Over time, the condition persists lifelong, with episodes potentially decreasing in frequency during adulthood but remaining responsive to provoking factors such as surgery. The severity of bleeding varies considerably among patients, influenced by the degree of integrin deficiency. Mild cases may present with only occasional epistaxis or minor bruising, while severe forms involve frequent and profuse hemorrhages that can require medical intervention. In pediatric populations, epistaxis is reported in 60-80% of cases and often leads to hospitalization, whereas gingival bleeding affects up to 60%. Specific examples of severe manifestations include postpartum hemorrhage in women, which can be life-threatening and necessitate transfusions, and arising from mucosal telangiectasias, occurring in 10-28% of patients. Post-dental extraction or surgical is also common, highlighting the disorder's impact on invasive procedures.

Complications

Patients with Glanzmann's thrombasthenia (GT) often develop due to chronic blood loss from recurrent mucocutaneous . This complication is particularly common in females experiencing , leading to insidious onset and necessitating regular monitoring of levels to prevent severe fatigue and growth impairment. In pediatric cases, iron supplementation and management are essential to mitigate anemia-related morbidity. Life-stage specific risks include excessive bleeding during menstruation, , and delivery. affects nearly all females with GT, exacerbating and requiring targeted interventions like hormonal therapy or . poses heightened risks of antepartum, intrapartum, and postpartum hemorrhage, with bleeding episodes reported in up to 22% of cases, often managed with platelet transfusions or . Affected neonates face increased hemorrhage risk, particularly from alloimmunization if the mother has developed antibodies or if the infant inherits the disorder, potentially leading to intracranial events in severe cases. Perioperative hemorrhage is a major concern during surgeries such as or , where platelet transfusions are frequently required to achieve and prevent excessive blood loss. Rare severe events encompass , occurring in approximately 1-2% of patients, which can be life-threatening and often requires urgent neurosurgical intervention. , often due to or telangiectasias, is reported in 10-20% of cases. Repeated platelet transfusions for bleeding control can induce alloimmunization, resulting in refractoriness that complicates future transfusions and increases reliance on alternative therapies like . Long-term impacts include potential developmental delays in children stemming from chronic and recurrent hospitalizations, though such associations are emerging and require further study. effects arise from activity restrictions to avoid injury, leading to school absences in 38% of pediatric patients and diminished , with females reporting greater emotional distress from bleeding episodes. Untreated severe cases carry a higher mortality primarily from uncontrollable hemorrhage.

Etiology and Pathophysiology

Genetic Causes

Glanzmann's thrombasthenia is an autosomal recessive bleeding disorder requiring biallelic pathogenic variants in either the ITGA2B or ITGB3 gene for disease manifestation, with unaffected heterozygous carriers typically asymptomatic. The genes are located in close proximity on 17q21, with ITGA2B (at 17q21.31) encoding the αIIb integrin subunit and ITGB3 (at 17q21.32) encoding the β3 subunit, which together form the platelet fibrinogen receptor essential for aggregation. Mutations in these genes account for over 90% of cases, with the disorder showing no sex predilection due to its autosomal inheritance pattern. The mutation spectrum is highly diverse, with more than 500 distinct pathogenic variants reported across both genes as of 2024, including missense (the most common type, comprising approximately 50% of cases), , frameshift, splice-site alterations, small insertions/deletions, and rare large genomic deletions. Certain populations have founder variants, such as the ITGA2B c.1561_1567del mutation in Iraqi . These variants lead to three main phenotypic subtypes based on αIIbβ3 expression levels: type I (complete deficiency, <5% surface expression, representing 70-80% of cases), type II (partial deficiency, 5-20% expression, 10-15% of cases), and type III (also known as the variant form, with normal or near-normal expression but dysfunctional protein, 5-10% of cases). The global incidence is estimated at 1 in 1,000,000 births, though it rises to as high as 1 in 200,000 in some regions with high consanguinity rates, such as South Asian populations (e.g., southern Indian Hindus) and certain Jewish communities (e.g., Iraqi , where the carrier frequency approaches 1 in 44). Carrier frequencies are generally low worldwide (less than 1 in 500) but significantly higher in consanguineous groups, underscoring the role of endogamy in disease prevalence. Genetic counseling is recommended for affected families and at-risk populations, emphasizing recurrence risks of 25% per pregnancy for unaffected carriers. Prenatal diagnosis is feasible through chorionic villus sampling or amniocentesis to detect biallelic mutations, while carrier screening via targeted sequencing of ITGA2B and ITGB3 is advised in communities with known founder variants or high consanguinity to facilitate informed reproductive decisions.

Molecular Pathophysiology

Glanzmann's thrombasthenia is characterized by a core defect in the αIIbβ3 , also known as (GPIIb/IIIa), which is abundantly expressed on the platelet surface with approximately 80,000–100,000 copies per resting platelet. This functions as a calcium-dependent heterodimer composed of noncovalently associated αIIb and β3 subunits, enabling platelets to bind soluble fibrinogen and other adhesive ligands only upon activation-induced conformational change from a low-affinity bent state to a high-affinity extended state. In affected individuals, quantitative deficiency or qualitative dysfunction of αIIbβ3 prevents this ligand binding, thereby abolishing the critical bridge formation between adjacent platelets that is essential for stable development. Platelet aggregation fails in Glanzmann's thrombasthenia despite preserved initial adhesion to the subendothelium, which occurs normally via the GPIb-IX-V complex binding under high shear conditions. However, subsequent responses to physiological agonists such as ADP, , and are absent, as these stimuli cannot trigger αIIbβ3 activation to support fibrinogen-mediated cross-linking and platelet clumping. Ristocetin-induced aggregation remains intact because it relies on GPIb-IX-V rather than αIIbβ3, highlighting the specificity of the defect. Additionally, clot retraction is impaired due to the inability of activated αIIbβ3 to link platelets to strands, further compromising stability. This molecular disruption leads to defective primary , manifesting as prolonged because platelets cannot form a robust plug at sites of vascular . A secondary effect involves reduced exposure of procoagulant phospholipids on the platelet surface, as αIIbβ3-mediated cytoskeletal reorganization is necessary for externalization that supports generation and formation. The condition is classified into variants based on αIIbβ3 expression and function: Type I features absent protein expression (<5% of normal levels), resulting in a complete loss of integrin on the platelet surface; Type II shows reduced quantity (5–20% of normal), with partial but insufficient functional receptors; and Type III (variants) exhibits normal or near-normal quantities but conformational abnormalities that prevent ligand binding despite preserved surface presence. The shared β3 subunit also pairs with αv to form the αvβ3 integrin on platelets and other cells, potentially contributing to phenotypic variations by affecting additional adhesive functions beyond hemostasis. Animal models, particularly β3-integrin knockout mice, recapitulate the bleeding phenotype of Glanzmann's thrombasthenia, with deficient mice displaying impaired platelet aggregation, prolonged tail bleeding times, and spontaneous hemorrhages that confirm the causality of αIIbβ3 loss in hemostatic failure. These models further demonstrate preserved platelet adhesion but absent aggregation responses to agonists, mirroring human pathophysiology.

Diagnosis

Clinical Evaluation

The clinical evaluation of suspected Glanzmann's thrombasthenia begins with a thorough , focusing on the onset of bleeding symptoms typically manifesting in infancy or , often within the first few months to years of life. Key historical elements include recurrent mucocutaneous episodes, such as epistaxis or gingival hemorrhage, exacerbated by procedures like or dental extractions, alongside an absence of hemarthroses or deep muscle bleeds that would suggest hemophilia. A family history of or similar bleeding disorders is particularly suggestive, given the autosomal recessive inheritance pattern, and should prompt heightened suspicion in high-prevalence ethnic groups such as those of Iraqi Jewish, , or South Asian descent. Physical examination reveals characteristic mucocutaneous findings, including petechiae, purpura, and ecchymoses on the skin and , without evidence of or . The severity of bleeding is quantitatively assessed using standardized tools like the International Society on Thrombosis and Haemostasis (ISTH) Bleeding Assessment Tool (BAT), which helps score the extent of hemorrhagic symptoms and guides diagnostic . Red flags include a lifelong pattern of easy bruising and prolonged after minor trauma, without associated coagulopathies or , warranting urgent evaluation to rule out life-threatening hemorrhage risks. Differential diagnosis involves distinguishing Glanzmann's thrombasthenia from other mucocutaneous bleeding disorders, such as (differentiated by normal response), Bernard-Soulier syndrome (characterized by giant platelets), immune thrombocytopenia (marked by low platelet count), and acquired platelet function defects (typically lacking a congenital history). Initial management steps emphasize avoiding elective invasive procedures to prevent exacerbation of bleeding until confirmation, with prompt referral to a hematologist for specialized assessment.

Laboratory Tests

Laboratory diagnosis of Glanzmann's thrombasthenia (GT) begins with routine tests, which typically reveal a normal platelet count, often at the lower end of the normal range (150–450 × 10^9/L), and normal platelet morphology on peripheral . Platelet function analyzer () closure times are extended with /ADP or /epinephrine cartridges, though it has limited specificity and is considered optional by the International Society on Thrombosis and Haemostasis (ISTH) due to this limitation. Coagulation studies, including (PT) and activated (aPTT), are normal, helping to exclude coagulopathies like hemophilia. Platelet function testing is central to confirming GT. Light transmission aggregometry (LTA), the gold standard, demonstrates absent or severely reduced aggregation in response to (ADP), epinephrine, , and , but normal aggregation with , which tests Ib-IX-V function. quantifies surface expression of the αIIbβ3 (CD41/CD61), showing reduced or absent levels in most cases (types I and II GT, with <5% and 5–20% expression, respectively), while CD42b ( Ib) is normal; in type III (variant) GT, expression is normal but function is impaired. Activation-dependent assays, such as binding of PAC-1 (a to the activated αIIbβ3) or fibrinogen, confirm defective activation. In vitro clot retraction is absent or markedly impaired due to the role of αIIbβ3 in platelet-mediated clot stabilization. Genetic confirmation involves bidirectional sequencing of the ITGA2B (encoding αIIb) and ITGB3 (encoding β3) genes to identify biallelic mutations leading to absent or reduced expression in most cases (types I and II); large deletions/duplications may require additional methods like . Variants are classified as pathogenic, likely pathogenic, or variants of uncertain significance using American College of Medical Genetics and (ACMG) guidelines, adapted by the ClinGen Platelet Disorders Expert Panel for these genes to improve specificity in autosomal recessive GT. Advanced are used selectively. The immobilization of platelet antigens (MAIPA) can help characterize type III variants by assessing functional epitopes, though it is more commonly employed to detect anti-αIIbβ3 alloantibodies in transfused patients. of platelets typically shows normal , including preserved dense granules, but may rarely reveal subtle abnormalities in distribution. Diagnostic criteria require a combination of clinical bleeding history, absent platelet aggregation on LTA, confirmatory or , and exclusion of acquired mimics like autoantibodies. In resource-limited settings, diagnosis is challenging due to limited access to specialized platelet function labs and genetic sequencing, often leading to underdiagnosis and reliance on prolonged alone.

Management

Supportive Treatments

Patients with Glanzmann's thrombasthenia are advised to avoid aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and antiplatelet agents to prevent exacerbation of bleeding tendencies, as these impair residual platelet function. For minor bleeding episodes, local hemostatic measures such as direct pressure application for at least 10 minutes, fibrin sealants, or topical are recommended to achieve control without systemic intervention. Pharmacologic management primarily involves to stabilize clots in mucosal bleeding sites, such as epistaxis or oral hemorrhage. , administered orally or intravenously at 10-25 mg/kg every 8 hours (up to 1 g every 8 hours in adults), or ε-aminocaproic acid at 50-100 mg/kg every 4-6 hours (maximum 24 g/day), is effective for these indications and can be used for 7-10 days. For severe or refractory bleeding, recombinant activated factor VII (rFVIIa) is administered at doses of 90-120 μg/kg intravenously every 2 hours, with at least three doses to promote generation on platelet surfaces and achieve . Transfusion therapy with HLA-matched platelets is reserved for life-threatening bleeds or when other measures fail, typically limited to fewer than 3-5 lifetime exposures to minimize the risk of alloimmunization and refractoriness. Dosing involves 10-15 mL/kg in children or one adult unit, administered every 12-24 hours as needed, with close monitoring for development. In surgical or dental procedures, prophylactic administration of rFVIIa (≥80-120 μg/kg 10-60 minutes preoperatively, repeated as required) or HLA-matched platelets (1-2 hours preoperatively) is standard to prevent excessive blood loss, often in combination for major interventions. For menorrhagia, hormonal therapies such as combined oral contraceptives are employed to regulate menstrual cycles and reduce bleeding volume. Pregnancy management requires a multidisciplinary team involving hematologists and obstetricians, with antifibrinolytics like (1 g post-delivery and every 8 hours as needed) and rFVIIa (80-120 μg/kg during labor) used prophylactically for , which is preferred unless obstetric indications necessitate cesarean section. Platelet transfusions are avoided antenatally to prevent but may be considered peripartum if severe hemorrhage occurs and antibodies are absent. Postpartum, is continued for at least two weeks, and low-progesterone contraception is initiated to mitigate secondary hemorrhage risks.

Advanced and Emerging Therapies

(HSCT) represents a curative option for severe cases of Glanzmann's thrombasthenia (GT), particularly in young s with life-threatening bleeding or alloantibody development against platelet transfusions. This approach typically involves allogeneic HSCT from HLA-matched donors, often siblings, using myeloablative conditioning regimens to achieve engraftment of donor hematopoietic stem cells, which restore production of functional platelets expressing the αIIbβ3 . Successful engraftment leads to normalization of platelet aggregation and bleeding times, with sustained clinical improvement reported in pediatric cases for over five years post-transplant. In children, success rates exceed 90% when using matched donors, though overall outcomes vary based on donor type and age, with one multicenter reporting an 80% overall among five allogeneic HSCT recipients followed for a mean of 18 years. Key risks include , infections, and transplant-related mortality, necessitating careful selection and supportive care. Gene therapy for GT is in preclinical and early-phase development, focusing on lentiviral vectors to deliver functional copies of the ITGA2B and ITGB3 genes into autologous hematopoietic stem cells, enabling expression of the missing αIIbβ3 on platelets. These vectors target long-term repopulating cells, with preclinical models demonstrating stable transduction and correction of platelet aggregation defects without disrupting normal hematopoiesis. At the 2024 American Society of Hematology () Annual Meeting, researchers presented data on optimized human-grade lentiviral vectors that achieved sustained αIIbβ3 expression in nonhuman models and human cell lines, supporting progression toward clinical trials. Challenges include ensuring vector safety, achieving sufficient transduction efficiency, and avoiding , but advances in vector design have improved specificity to lineages. Novel biologics are emerging as potential prophylactic therapies to bridge the gap toward curative options. Sutacimig (formerly HMB-001), a bispecific engineered to mimic fibrinogen binding and activate platelets independently of the defective αIIbβ3, has completed a phase 1/2 (NCT06211634). Interim results from this multinational study, fully enrolled by mid-2025 with 34 patients, showed a greater than 50% reduction in treated bleeding episodes across dose levels, with a favorable safety profile and no thromboembolic events reported. The 's mechanism involves targeted delivery of activated factor VII to injury sites, enhancing without relying on platelet transfusions. Pharmacokinetic and efficacy data from the phase 1/2 confirm dose-dependent prolongation of clot formation in GT patient plasma. Following successful completion of the trial in 2025, a pivotal registration is planned for 2026. Other investigational approaches include gene modification of platelet glycoproteins using viral vectors or CRISPR-based editing to restore partial αIIbβ3 function in patient-derived megakaryocytes, though these remain preclinical due to scalability issues. Small molecules aimed at enhancing residual activity or stabilizing low-level αIIbβ3 expression are also in early exploration, with in vitro studies showing promise in variant-specific GT subtypes. A major challenge is off-target effects on β3 integrins in vascular , which could lead to unintended prothrombotic or anti-angiogenic outcomes, requiring refined specificity in therapeutic design. Future directions emphasize multinational registries, such as the International Prospective Glanzmann Thrombasthenia Registry, to facilitate trial recruitment and long-term outcome tracking for rare variants. approaches, tailored to specific ITGA2B/ITGB3 mutations, hold potential for optimizing HSCT conditioning or selecting vectors, with ongoing genomic studies informing variant-phenotype correlations to guide therapy selection.

History and Nomenclature

Eduard Glanzmann (1887–1959) was a Swiss pediatrician renowned for his contributions to and , where he served as a professor at the . In 1918, Glanzmann published a seminal description of the disorder in Jahrbuch für Kinderheilkunde, coining the term "hereditary hemorrhagic thrombasthenia" to characterize the condition observed in children from a village in the ; the name "thrombasthenia" derives from thrombos (clot) and asthenia (weakness), reflecting the observed platelet dysfunction. Glanzmann's observations preceded the detailed understanding of platelet and aggregation, establishing his pivotal role in the early of inherited thrombocytopathies, for which the disease bears his . The "Glanzmann's thrombasthenia" continues in widespread use today, alongside the more descriptive designation " αIIbβ3 deficiency," even as broader medical discussions debate the merits of eponymous in favor of etiology-based terms.

Historical Development

Glanzmann's thrombasthenia was first described in 1918 by Swiss pediatrician Eduard Glanzmann, who reported six cases of children exhibiting prolonged times and defective clot retraction despite normal platelet counts, attributing the condition to inherently weak platelets or "thrombasthenia." In the 1950s and early 1960s, French researchers Marie-Jeanne Larrieu and Jean-Pierre Caen advanced understanding through studies on platelet function, confirming aggregation defects in affected patients using rudimentary optical methods that preceded modern aggregometers. Their 1966 report on 15 cases solidified the clinical and biological features, including absent platelet aggregation in response to (ADP) and other agonists, distinguishing the disorder from other diatheses. During the mid-20th century, particularly in the and , the condition was formally classified as thrombasthenia based on these functional impairments, with aggregation studies using early platelet aggregometers developed by Gustav Born in providing key evidence of failed platelet clumping. A pivotal discovery occurred in 1974 when Alan Nurden and Jean-Pierre Caen utilized sodium dodecyl sulfate-polyacrylamide to identify the absence of two major platelet glycoproteins, later designated GPIIb and GPIIIa (now αIIb and β3 ), in thrombasthenic platelets from three patients, linking the disorder to a specific receptor deficiency. The molecular era began in the late 1980s with the cloning of the genes encoding these glycoproteins: ITGA2B (for αIIb) was cloned in 1987 by Poncz et al., followed by ITGB3 (for β3) in 1987 by Fitzgerald et al., enabling genetic analysis of the disorder. The first reports of specific mutations appeared in 1992, with Ruan et al. describing compound heterozygous variants in ITGA2B, including a premature stop codon and a splicing defect, in a patient with absent GPIIb expression. In the 2000s, advancements in flow cytometry facilitated variant typing into types I (less than 5% surface expression), II (5-20%), and III (normal expression but dysfunctional receptor), refining diagnosis and correlating expression levels with bleeding severity. In the 2010s, the establishment of international registries, such as the prospective Glanzmann Thrombasthenia Registry (GTR) initiated in the early 2000s and expanded globally, collected data on over 200 patients to evaluate treatment outcomes and , highlighting geographic variations and management challenges. Entering the 2020s, research has intensified on trials, with preclinical and early-phase studies using lentiviral vectors to restore αIIbβ3 expression in megakaryocytes, alongside increased awareness of elevated prevalence in consanguineous populations, which account for up to 80% of cases in certain regions. Additionally, as of 2025, Hemab Therapeutics' investigational HMB-001, targeting the αIIbβ3 , has entered Phase 1/2 clinical trials, showing encouraging results in reducing bleeding episodes in patients with GT. This evolution reflects a shift from empirical platelet transfusions—plagued by alloimmunization risks—to targeted therapies like standardized recombinant activated factor VII (rFVIIa), with post-2010 data from registries demonstrating its efficacy in controlling bleeding in over 90% of episodes.

References

  1. https://www.ncbi.nlm.nih.gov/books/NBK538270/
  2. https://medlineplus.gov/genetics/condition/glanzmann-thrombasthenia/
  3. https://www.hemab.com/news-items/hemab-therapeutics-presents-positive-phase-1-results-for-hmb-001-in-glanzmann-thrombasthenia-at-2024-eahad-annual-congress
  4. https://rarediseases.org/rare-diseases/glanzmann-thrombasthenia/
  5. https://pmc.ncbi.nlm.nih.gov/articles/PMC8205616/
  6. https://haematologica.org/article/view/9325
  7. https://www.bloodresearch.or.kr/journal/view.html?doi=10.5045/br.2021.2021165
  8. https://pubmed.ncbi.nlm.nih.gov/35412688/
  9. https://www.rarediseaseadvisor.com/news/bleeding-management-glanzmanns-thrombasthenia-may-reduce-fnait-risk/
  10. https://ashpublications.org/blood/article-abstract/139/17/2632/484395
  11. https://haematologica.org/article/view/8126
  12. https://pmc.ncbi.nlm.nih.gov/articles/PMC10542831/
  13. https://wiley.authorea.com/users/936105/articles/1306467-a-novel-association-between-glanzmann-thrombasthenia-and-psychomotor-delay-a-case-report
  14. https://www.dovepress.com/disease-burden-in-patients-with-glanzmannrsquos-thrombasthenia-perspec-peer-reviewed-fulltext-article-JBM
  15. https://omim.org/entry/273800
  16. https://www.nature.com/articles/ejhg2012151
  17. https://pmc.ncbi.nlm.nih.gov/articles/PMC7109743/
  18. https://www.nature.com/articles/s41525-019-0079-6
  19. https://www.mdpi.com/2079-9721/12/7/136
  20. https://www.sciencedirect.com/science/article/pii/S088779631600002X
  21. https://pubmed.ncbi.nlm.nih.gov/6531749/
  22. https://fulgentgenetics.com/content/flyer/FLY-Beacon-Supplementary-Table-V7.pdf
  23. https://pmc.ncbi.nlm.nih.gov/articles/PMC4501245/
  24. https://doi.org/10.1182/blood-2011-07-365635
  25. https://doi.org/10.1182/blood-2008-06-077891
  26. https://doi.org/10.1172/JCI108805
  27. https://pmc.ncbi.nlm.nih.gov/articles/PMC407888/
  28. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4501245/
  29. https://emedicine.medscape.com/article/200311-clinical
  30. https://pubmed.ncbi.nlm.nih.gov/16420557/
  31. https://pubmed.ncbi.nlm.nih.gov/33496739/
  32. https://ashpublications.org/blood/article/139/17/2632/484395/How-I-manage-pregnancy-in-women-with-Glanzmann
  33. https://www.cureus.com/articles/299502-bleeding-phenotype-of-glanzmann-thrombasthenia-gt-and-treatment-outcomes-in-over-one-hundred-patients-a-two-center-experience-in-north-pakistan
  34. https://emedicine.medscape.com/article/200311-treatment
  35. https://journals.lww.com/jaht/fulltext/2019/10010/management_of_glanzmann_s_thrombasthenia__.1.aspx
  36. https://pmc.ncbi.nlm.nih.gov/articles/PMC10311872/
  37. https://pmc.ncbi.nlm.nih.gov/articles/PMC8859262/
  38. https://pmc.ncbi.nlm.nih.gov/articles/PMC4011384/
  39. https://pmc.ncbi.nlm.nih.gov/articles/PMC11646327/
  40. https://pubmed.ncbi.nlm.nih.gov/14629461/
  41. https://www.nature.com/articles/s44161-023-00418-4
  42. https://clinicaltrials.gov/study/NCT06211634
  43. https://www.prnewswire.com/news-releases/hemab-therapeutics-presents-positive-clinical-and-preclinical-data-across-bleeding-disorder-pipeline-at-isth-2025-congress-302488365.html
  44. https://sofinnovapartners.com/news/hemab-therapeutics-announces-usd157-million-series-c-financing-to-advance-next-generation-treatments-for-underserved-bleeding-disorders
  45. https://www.dovepress.com/profiling-the-genetic-and-molecular-characteristics-of-glanzmann-throm-peer-reviewed-fulltext-article-JBM
  46. https://pmc.ncbi.nlm.nih.gov/articles/PMC5004418/
  47. https://litfl.com/eduard-glanzmann/
  48. https://www.healio.com/news/hematology-oncology/20120325/guido-fanconi-and-eduard-glanzmann-pioneers-in-pediatric-hematology
  49. https://ojrd.biomedcentral.com/articles/10.1186/1750-1172-1-10
  50. https://www.thebloodproject.com/eponyms-in-hematology-glanzmann-thrombasthenia/
  51. https://www.hog.org/handbook/section/1/glanzmann-thrombasthenia
  52. https://haematologica.org/article/view/haematol.2023.282836
  53. https://pubmed.ncbi.nlm.nih.gov/11197210/
  54. https://med.stanford.edu/news/insights/2020/01/eponym-debate-the-case-for-naming-diseases-after-people.html
  55. https://pmc.ncbi.nlm.nih.gov/articles/PMC2872751/
  56. https://pubmed.ncbi.nlm.nih.gov/14462482/
  57. https://www.sciencedirect.com/science/article/pii/0002934366900039
  58. https://pubmed.ncbi.nlm.nih.gov/4473996/
  59. https://omim.org/entry/607759
  60. https://pubmed.ncbi.nlm.nih.gov/1317725/
  61. https://pmc.ncbi.nlm.nih.gov/articles/PMC5004419/
  62. https://www.bleeding.org/news/investigational-data-on-vwd-and-glanzmann-thrombasthenia-therapies-presented-at-isth
  63. https://www.clinicaltrialsarena.com/news/hemab-glanzmann-thrombasthenia-trial/
Add your contribution
Related Hubs
User Avatar
No comments yet.