Outcomes of recombinant activated factor VIIa (NovoSeven) therapy in glanzmann thrombasthenia: two case reports

Abstract

Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet function disorder resulting from qualitative or quantitative defects in the GPIIb/IIIa (integrin αIIbβ3) complex. Patients typically present with mucocutaneous bleeding. Standard treatment involves antifibrinolytic agents and platelet transfusions; however, repeated transfusions may lead to alloimmunization and platelet refractoriness. Recombinant activated factor VIIa (rFVIIa; NovoSeven) offers an alternative hemostatic approach. We present two pediatric cases of GT managed with rFVIIa. The first case involves a 12-year-old female with a strong family history of GT, who initially responded well to rFVIIa prophylaxis but later experienced increased bleeding episodes during puberty. The second case is a 20-year-old male with a history of mucocutaneous bleeding, who achieved long-term bleeding control on regular rFVIIa prophylaxis. Both patients demonstrated reduced bleeding frequency and improved quality of life without thromboembolic complications. These cases underscore the therapeutic potential and safety of rFVIIa in managing bleeding episodes and preventing alloimmunization in GT, particularly when platelet transfusions are ineffective or contraindicated, and highlight the importance of individualized treatment approaches and the need for further research to refine prophylactic regimens in GT.

Introduction

Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet function disorder characterized by impaired platelet aggregation despite normal platelet count and morphology. The condition results from qualitative or quantitative defects in the platelet glycoprotein IIb/IIIa (integrin αIIbβ3) complex, which serves as the principal receptor for fibrinogen and other adhesive ligands necessary for platelet cross-linking and thrombus formation [1–3]. Consequently, individuals with GT exhibit defective primary hemostasis and are prone to mucocutaneous bleeding of variable severity [1,7].

Clinical manifestations typically emerge in infancy or early childhood and include epistaxis, gingival bleeding, purpura, and menorrhagia in females [1,2,4,7]. The severity and frequency of bleeding episodes can vary widely and are often disproportionate to the inciting event due to the underlying platelet dysfunction [7,8]. While local measures and antifibrinolytics may control mild bleeding, platelet transfusion remains the mainstay for managing moderate to severe hemorrhage and perioperative bleeding [2,4]. However, repeated transfusions carry the risk of alloimmunization, particularly the development of anti-HLA or anti-GPIIb/IIIa antibodies, which can result in platelet refractoriness and therapeutic failure [5,6].

Recombinant activated factor VIIa (rFVIIa; NovoSeven) has emerged as a bypassing agent capable of promoting hemostasis in GT patients with or at risk for alloimmunization. Its mechanism involves direct activation of factor X on the surface of activated platelets, facilitating thrombin generation independent of the dysfunctional GPIIb/IIIa pathway [7–9]. Accumulating evidence supports the efficacy of rFVIIa in both therapeutic and prophylactic settings, particularly in cases refractory to conventional management.

This report presents two pediatric cases of GT – one in a female adolescent with hormonally triggered bleeding and another in a young adult male – both successfully managed with rFVIIa. The cases underscore the utility of rFVIIa in complex clinical scenarios and highlight its role as a nontransfusion-based strategy in patients requiring long-term bleeding control.

Case presentations

Case 1

A 12-year-old female was diagnosed with Glanzmann thrombasthenia (GT) shortly after birth. She presented with extensive cutaneous bruising and facial petechiae at birth, requiring admission to the neonatal intensive care unit (NICU). Initial laboratory findings revealed severe thrombocytopenia, prompting urgent platelet transfusions over ten consecutive days to mitigate the risk of intracranial hemorrhage.

The family history was notable for consanguinity and multiple affected siblings, including one confirmed GT diagnosis and another who died from neonatal intracranial hemorrhage. Platelet aggregation studies confirmed absent aggregation in response to adenosine diphosphate (ADP), collagen, and epinephrine, with preserved response to ristocetin, confirming GT.

During childhood, she experienced frequent mucocutaneous bleeding, including epistaxis and gingival hemorrhage, managed with antifibrinolytics including oral tranexamic acid and intermittent platelet transfusions. Due to increasing transfusion dependency and bleeding frequency, prophylactic recombinant activated factor VIIa (rFVIIa; NovoSeven) was initiated at a dose of 90 μg/kg twice weekly. The patient showed a favorable response and a marked reduction in bleeding episodes and improvement in functional status.

However, in recent months, she developed recurrent epistaxis and prolonged menorrhagia associated with symptomatic anemia, necessitating red blood cell transfusions. Evaluation excluded structural lesions, infection, or treatment nonadherence. The exacerbation was attributed to hormonal changes at puberty. Hematopoietic stem cell transplantation (HSCT) was considered, but no suitable HLA-matched donor was available.

Case 2

A 20-year-old male, diagnosed with GT at age four, presented with ecchymoses on lower limb and facial petechiae. Physical examination was unremarkable apart from minor nasal abrasions. Platelet count and morphology were normal, but bleeding time was prolonged. Aggregation studies demonstrated absent responses to ADP and collagen, with normal response to ristocetin, confirming the diagnosis of GT.

His family history suggested a hereditary platelet disorder, though detailed family records were limited. Notably, his father has schizophrenia, which contributed to gaps in medical history and reduced the reliability of familial data.

The patient's early management included platelet transfusions and antifibrinolytic agents for frequent mucocutaneous bleeds, particularly epistaxis. Due to increasing transfusion requirements and the risk of alloimmunization, prophylactic rFVIIa was initiated at age 14, receiving 90 μg/kg twice weekly. The patient responded favorably, with significant reductions in bleeding frequency and stabilization of hemoglobin levels.

He continues to receive maintenance rFVIIa prophylaxis with no thromboembolic complications and remains clinically stable under routine hematologic follow-up.

Discussion

GT is a rare inherited platelet function disorder caused by quantitative or qualitative defects in the GPIIb/IIIa (integrin αIIbβ3) complex, a critical mediator of platelet aggregation. Despite normal platelet counts and morphology, patients with GT exhibit defective platelet plug formation, predisposing them to spontaneous mucocutaneous bleeding.

While antifibrinolytics and local hemostatic measures can be effective for minor bleeding, platelet transfusions remain the cornerstone for managing moderate to severe hemorrhage and for perioperative prophylaxis [2,4]. However, repeated transfusions increase the risk of alloimmunization against HLA and/or GPIIb/IIIa antigens, which may lead to platelet refractoriness and pose significant challenges in bleeding control [4–6]. This underscores the need for alternative nontransfusion-based therapies in GT patients with transfusion complications or in those requiring frequent interventions.

Recombinant activated factor VIIa (rFVIIa; NovoSeven) acts independently of platelet GPIIb/IIIa by directly activating factor X on the surface of activated platelets, thereby facilitating thrombin generation and fibrin clot formation [7–9]. Its efficacy in GT has been demonstrated in both surgical and nonsurgical settings, particularly in patients with alloantibody-mediated refractoriness [3,11]. Several registries and clinical reports support its use for both on-demand bleeding control and prophylaxis [9–11].

In the current report, both patients benefited from prophylactic rFVIIa, which led to significant reductions in bleeding frequency and transfusion requirements. In Case 1, the adolescent female initially responded well but experienced recurrent epistaxis and menorrhagia during puberty. In the absence of infection or structural pathology, the clinical deterioration was attributed to hormonal fluctuations. Notably, adolescence and menarche represent high-risk periods for females with GT, and prophylaxis may require tailoring based on hormonal status [11,12]. The patient is currently under evaluation for HSCT, the only curative treatment for GT, although the lack of an HLA-matched donor remains a barrier [2,8].

In Case 2, the male patient exhibited excellent long-term response to rFVIIa prophylaxis, with sustained bleeding control and stabilization of hemoglobin levels. Importantly, no thromboembolic or hypersensitivity complications were observed during treatment, consistent with previous safety profiles [13,14]. This highlights rFVIIa's favorable risk–benefit ratio when used in appropriately selected patients under specialist supervision. These findings align with existing literature supporting the use of rFVIIa for both on-demand bleeding control and prevention in high-risk patients [9,11–13].

While rFVIIa is generally well tolerated, its use is not without risk. Rare but serious thrombotic complications have been reported, particularly in individuals with predisposing risk factors, along with occasional hypersensitivity reactions [13–15].

The optimal dosing regimen for prophylactic rFVIIa remains to be standardized, with most literature supporting doses ranging from 60 to 120 μg/kg administered two to three times weekly. In both cases presented here, a regimen of 90 μg/kg twice weekly was effective and well tolerated [3,12]. Individualized protocols based on bleeding phenotype, age, and treatment history remain essential.

These findings contribute to the growing body of evidence supporting the use of rFVIIa in GT patients with or at risk for alloimmunization. While rFVIIa does not replace curative approaches such as HSCT or emerging gene therapy, it offers a critical therapeutic option for maintaining hemostatic stability in patients for whom transfusion strategies are limited or ineffective [2,8].

Conclusion

These two pediatric cases of GT underscore the clinical utility of recombinant activated factor VIIa (rFVIIa; NovoSeven) as an effective hemostatic agent for both prophylactic and therapeutic use. In patients with transfusion-dependent bleeding or alloimmunization, rFVIIa provided sustained bleeding control, reduced transfusion burden, and improved quality of life without significant adverse effects. The favorable safety and efficacy profiles observed in both cases support its role as a viable alternative to platelet transfusions, particularly in patients with refractoriness or requiring long-term management.

Individualized prophylactic regimens with rFVIIa should be considered in high-risk populations, including adolescents and patients with limited access to curative options such as HSCT. Further prospective studies and real-world data are needed to optimize dosing strategies and to better define the long-term safety and outcomes associated with extended rFVIIa use in inherited platelet function disorders.

Acknowledgements

Written informed consent was obtained from legal guardians for the publication of any potentially identifiable images or data included in this article.

Author contributions: Dr Eman: Analysis, critical revision of manuscript and approval of final version. Dr Sondus: Analysis, critical revision of manuscript and approval of final version. Dr Omnia: Data acquisition, research design, and drafting of the manuscript.

Medical writing support: Medical writing support was provided by Al Essa Medical and Scientific Group.

Funding: The publication of this article is supported by NBK Children Specialized Hospital, Kuwait.

Conflicts of interest

The authors declare no conflicts of interest related to this case report.