Glanzmann thrombasthenia (GT) is a rare autosomal recessive bleeding disorder arising from quantitative or qualitative defects in the platelet glycoprotein (GP) IIb/IIIa complex (αIIbβ3 integrin). This receptor is essential for fibrinogen binding and platelet aggregation, and its dysfunction leads to impaired clot formation (1). First described in 1918 by Glanzmann, GT is considered rare in most populations but has higher prevalence in regions with consanguineous marriages, such as Jordan (2–5).

The clinical hallmark of GT is lifelong mucocutaneous bleeding, including epistaxis, gingival hemorrhage, and menorrhagia (6). Gastrointestinal (GI) bleeding is not an uncommon manifestation, reported in 10–20% of patients, and it can be severe, life-threatening, and unpredictable (7). GT diagnosis is confirmed by demonstrating absent or impaired platelet aggregation in response to ADP, collagen, and epinephrine, with normal ristocetin-induced agglutination (7–9). Flow cytometry shows absent or decreased CD41 (GPIIb) and CD61 (GPIIIa) expression, and genetic testing is crucial for definitive subtyping and counseling (7, 8).

GT is classified into three types: Type I (severe, <5% GPIIb/IIIa), Type II (moderate, 5–20% GPIIb/IIIa), and Type III (>20% to normal levels of dysfunctional protein) (10). Management of bleeding episodes is supportive, involving local measures such as cauterization, antifibrinolytics (e.g., tranexamic acid), and systemic therapies such as platelet transfusions or recombinant activated factor VII (rFVIIa) (11, 12). A significant long-term challenge is the development of antiplatelet antibodies, leading to platelet refractoriness (6).

We present a case series of six patients with type I GT who experienced upper GI bleeding. This report aims to clarify the heterogeneous presentation and management challenges of this complication, supplemented by a comprehensive review of the literature. All patients showed complete resolution of bleeding after supportive treatment.

A total of six individuals with GT experienced upper GI bleeding at the University of Jordan Hospital between 2010 and 2025. The individuals were invited to participate in this research protocol after the Institutional Ethics Committee had approved it (IRB/4/2017-17). Written informed consent was obtained from the patients. Data were obtained from medical records and confirmed by the patients.

Platelet aggregation testing was performed using multiple electrode aggregometry with the multiple platelet function analyzer (Multiplate^® Analyzer, Roche Diagnostics, Germany). Hirudin blood tubes were used, and the following agonists were applied: ADP 6.4 μM (ADPtest), collagen 3.2 μg/mL (COLtest), ristocetin 1.5 mg/mL (RISTO high), and 0.5 mg/mL (RISTO low).

Flow cytometry analysis was performed on whole blood to assess platelet surface glycoprotein expression (CD41 and CD61). Molecular studies included Sanger sequencing of the coding regions of the ITGB3 and ITGA2B genes. DNA was extracted from peripheral blood using a commercial kit (Qiagen MinElute, Germany). Samples were analyzed on an ABI 3500 Genetic Analyzer (Applied Biosystems, United States). Sequencing files were aligned to detect point mutations using Chromas Pro (Technelysium, Australia) against the reference transcript ENST00000559488.7. DNA variants were classified using an automated variant classification tool (https://franklin.genoox.com, accessed on 23 May 2025). Novel mutations were confirmed by their absence in any previously published studies.

We describe six patients with clinically confirmed type I GT who presented with upper GI bleeding. All patients had normal platelet counts and morphology, prolonged bleeding time (>13 min), poor clot retraction, and absent platelet aggregation in response to ADP and collagen, with normal aggregation in response to ristocetin. The flow cytometry findings were consistent with αIIbβ3 deficiency. Prior to the GI bleeding episodes, all patients had a history of recurrent mucocutaneous bleeding at various sites other than the GI tract and had received red blood cell and platelet transfusions. Key clinical characteristics and genetic results are summarized in Table 1.

Our case series illustrates the significant challenge of upper GI bleeding in GT, a complication that, while uncommon, can dominate the clinical course and lead to life-threatening anemia (13). The heterogeneity of our cases reflects the broader literature, where GI bleeding in GT can arise from diverse etiologies, including idiopathic mucosal oozing, discrete lesions, or vascular malformations (14–16).

A pivotal discussion point is the occurrence of GI bleeding in which the source and localization of bleeding could not be identified endoscopically, as observed in case 2. This phenomenon has been reported before (7, 17) and suggests diffuse vascular fragility inherent to the GT phenotype. The absence of the αIIbβ3 integrin may impair the integrity of the subepithelial vascular network or the initial platelet plug required to seal microscopic injuries, leading to significant bleeding from lesions that are invisible on conventional endoscopy (18).

Conversely, our case series also includes patients with identifiable structural causes. Case 4 had a bleeding polyp, exacerbated by NSAID use, highlighting the critical importance of avoiding antiplatelet agents in GT (19). Case 5 had a duodenal arteriovenous malformation (DAVM), a known association in GT (16, 20). The co-occurrence of a bleeding diathesis and vascular anomalies creates a perfect storm for severe hemorrhage. Other reported lesions include H. pylori-associated ulcers (21) and multiple gastric polyps requiring gastrectomy (22). This spectrum of findings underscores the need for a thorough endoscopic evaluation in any GT patient with GI bleeding, even when the mucosa appears grossly normal (20, 23).

The management of these episodes requires a multidisciplinary approach. Antifibrinolytic therapy with tranexamic acid is a cornerstone, reducing fibrinolytic activity at the mucosal surface (23). For major bleeding in previously transfused patients, rFVIIa has become an important agent for the treatment because the devolving of anti-platelets antibodies. It promotes thrombin generation on the surface of activated platelets independently of the IIb/IIIa receptor, effectively “bypassing” the defect (24). The high success rate (up to 91%) of rFVIIa, often combined with antifibrinolytics, is well documented in the GT registry (24). Its use is particularly advantageous in reducing the risk of alloimmunization associated with platelet transfusions, which is a well-recognized long-term complication in patients requiring repeated transfusions (6). The efficacy of this strategy is demonstrated in our series, where rFVIIa was used successfully in five of the six cases.

For refractory bleeding due to vascular anomalies, as described in the literature, advanced pharmacological agents include octreotide (to reduce splanchnic blood flow), thalidomide, and bevacizumab (anti-VEGF therapy) (16, 25). Hormonal therapy has also been used to reduce transfusion requirements in patients with diffuse vascular abnormalities (16). Although not required in our cases, these options represent important tools for complex scenarios. Ultimately, hematopoietic stem cell transplantation remains the only curative option for severe GT (26).

Genotype–phenotype correlations in patients suggest a possible link between specific ITGB3 variants and the severity of gastrointestinal bleeding in GT. However, the response to rFVIIa varies, showing differences in bleeding severity even among patients with the same genotype. Cases 1, 2, and 3, which experienced significant upper GI bleeding, carried the pathogenic missense mutation ITGB3 c.1723 T > C, a variant known to impair αIIbβ3 function (27). Case 6 experienced severe and progressive clinical GI bleeding and carried a likely pathogenic frameshift variant, ITGB3 c.783delG, which is expected to result in loss of protein expression. This strongly suggests that the frameshift mutation leads to more severe and complex GI bleeding compared to the missense mutation group. In contrast, two patients (Cases 4 and 5) who experienced GI bleeding showed no identifiable pathogenic or likely pathogenic point mutations in ITGB3, making it difficult to establish a genetic basis for their phenotype. Although the small sample size limits this correlation, these findings suggest that while certain ITGB3 mutations may contribute to a more severe bleeding profile, GI bleeding can still occur in the absence of detectable pathogenic variants.

Our findings, supported by evidence from the literature (Table 2), reinforce key management principles: Maintaining a high index of suspicion for GI bleeding, performing aggressive endoscopic localization and intervention when possible, and prioritizing rFVIIa over platelet transfusions to reduce the risk of alloimmunization. Eradication of H. pylori and strict avoidance of NSAIDs are essential prophylactic strategies.

Upper gastrointestinal bleeding is a severe and unpredictable complication of Glanzmann thrombasthenia. It can occur in the absence of visible mucosal lesions or in association with specific pathologies such as ulcers, polyps, or vascular malformations. Maintaining a high index of suspicion and performing prompt endoscopic evaluation are crucial. Management should be multifaceted, emphasizing the use of antifibrinolytics and rFVIIa as first-line systemic therapies in previously transfused patients to control bleeding effectively while minimizing the risk of platelet alloimmunization. For complex cases with vascular anomalies, advanced pharmacological agents provide additional options. Heightened awareness of this complication and a structured management approach are essential to mitigate the significant morbidity associated with GI bleeding in GT.