Recombinant Factor VIIa Prophylaxis in 2 Brothers with Bernard-Soulier Syndrome

Introduction

Bernard-Soulier Syndrome (BSS) is a rare inherited platelet disorder caused by genetic mutations affecting the glycoprotein 1b-IX-V complex, which is essential for normal platelet adhesion [1,2]. BSS has an estimated incidence of less than 1 per million live births, is typically diagnosed in infancy, and about 15–20% of patients present with severe forms.

The condition is usually inherited in an autosomal recessive pattern, though autosomal dominant cases with missense mutations have also been reported [3]. Clinically, BSS is characterized by thrombocytopenia, the presence of giant platelets, and mucocutaneous bleeding, such as epistaxis, easy bruising, menorrhagia, and prolonged bleeding following trauma or surgical procedures [4]. A landmark review by Lopez et al synthesizes the molecular basis of BSS (defects in the glycoprotein 1b-IX-V complex), diagnostic work-up (including flow cytometry and ristocetin-induced aggregation), and clinical heterogeneity, and remains a key reference informing contemporary diagnostic and management strategies [5].

The diagnosis of BSS is typically confirmed by flow cytometry and platelet aggregation studies showing absent aggregation in response to ristocetin – a finding that distinguishes BSS from immune thrombocytopenia. Management of BSS remains challenging, particularly in patients with severe bleeding tendencies [6,7]. Platelet transfusions are the mainstay of treatment but carry risks including alloimmunization and refractoriness, especially with repeated use [8,9].

Recombinant activated factor VIIa (rFVIIa; trade name: NovoSeven) has emerged as a potential therapeutic option in patients with platelet function disorders, including BSS, due to its ability to enhance thrombin generation and improve hemostasis independent of platelet adhesion mechanisms [10]. However, there is limited evidence regarding its prophylactic use in BSS.

Here, we present the case of 2 brothers with BSS who experienced a significant reduction in bleeding episodes following prophylactic treatment with rFVIIa [11,12]. The present report contributes to the growing body of evidence supporting rFVIIa as a viable therapeutic alternative in managing severe and recurrent bleeding in BSS [4,13].

Case Reports

CASE 1: OLDER BROTHER:

A 19-year-old male patient with a known diagnosis of BSS presented to the outpatient department with persistent gingival bleeding that had continued overnight. Initial home management using tranexamic acid-soaked gauze was unsuccessful. On examination, he was alert and oriented, with significant mucosal bleeding. Laboratory evaluation revealed anemia and thrombocytopenia. Hemoglobin and platelet counts were closely monitored; however, detailed values are not tabulated because they fluctuated with active bleeding and interval transfusions and did not reliably reflect the prophylactic effect of rFVIIa. We therefore focused on outcomes of clinical relevance – bleeding frequency/severity and hospitalizations (Table 1). He was admitted and treated with platelet transfusions and intravenous rFVIIa, which successfully controlled the bleeding.

The patient had been diagnosed with BSS at 2 years of age and had a longstanding history of mucocutaneous bleeding 2–3 times per week, particularly recurrent gingival hemorrhages, leading to multiple hospitalizations. Previous treatments included intravenous tranexamic acid and platelet transfusions, administered 3–4 times per year depending on bleeding severity. He had been prescribed iron supplementation for anemia secondary to chronic blood loss, but discontinued it without medical advice.

Family history was notable for parental consanguinity but the parents had no known bleeding disorders. However, his younger brother had also been diagnosed with BSS.

CASE 2: YOUNGER BROTHER:

An 18-year-old male patient, the younger sibling of the patient in Case 1, was diagnosed with BSS at 6 weeks of age following presentation with thrombocytopenia and hyperbilirubinemia. His clinical course was complicated by neurological symptoms, including kinetic tremors, ataxia, and bilateral hearing impairment, for which he was fitted with hearing aids. On physical examination, he was alert but exhibited clumsiness and had multiple ecchymotic patches over his chin and lower extremities. Laboratory investigations confirmed thrombocytopenia. Hemoglobin and platelet counts were closely monitored; however, detailed values are not tabulated because they fluctuated with active bleeding and interval transfusions and did not reliably reflect the prophylactic effect of rFVIIa. We therefore focused on outcomes of clinical relevance – bleeding frequency/severity and hospitalizations (Table 1).

Postoperatively, he was prescribed tranexamic acid mouthwash (30 mg/kg every 8 hours).

INITIATION OF PROPHYLACTIC TREATMENT:

Due to their history of frequent and severe bleeding episodes, both brothers were started on long-term prophylactic therapy with rFVIIa. The older brother received 4.5 mg (90 mcg/kg) intravenously once weekly, while the younger brother received 4 mg, also intravenously. The specific dosing schedule was tailored to each patient’s clinical needs and aimed at preventing spontaneous mucocutaneous bleeding.

MANAGEMENT OF ACUTE BLEEDING EPISODES:

For breakthrough or major bleeding events, the recommended therapeutic regimen consisted of 3 doses of rFVIIa at 90 mcg/kg administered over 6 hours (2 hours apart). This was used on an as-needed basis in addition to the prophylactic regimen.

Supportive care for both patients included oral iron supplementation to treat iron-deficiency anemia and vitamin D replacement as indicated.

FOLLOW-UP AND OUTCOMES:

Following initiation of prophylactic NovoSeven, both patients demonstrated a marked reduction in bleeding frequency and severity. At scheduled reviews, a sustained benefit was documented at 18 weeks for Patient 1 and 24 weeks for Patient 2. At follow-up, neither patient required further hospitalizations for bleeding-related complications, and both continue to receive prophylactic rFVIIa therapy with favorable outcomes. Table 1 compares Case 1 and Case 2.

Discussion

BSS is a rare inherited platelet disorder characterized by macrothrombocytopenia and defective platelet adhesion due to mutations affecting the glycoprotein 1b-IX-V complex [1,2]. This condition typically presents with mucocutaneous bleeding, including epistaxis, easy bruising, menorrhagia, and prolonged bleeding following trauma or surgical procedures. Diagnosis is confirmed through peripheral blood smear and platelet aggregation studies, with absent aggregation in response to ristocetin serving as a key diagnostic feature [6,7].

The management of BSS poses significant clinical challenges, particularly in patients with severe bleeding tendencies. Platelet transfusions remain the standard treatment for acute hemorrhage but carry risks of alloimmunization and transfusion refractoriness, especially when used repeatedly. These complications highlight the need for alternative therapeutic strategies that minimize reliance on platelet products [8,9].

From a broader therapeutic perspective, BSS management spans supportive and interventional measures. Platelet transfusions remain the standard for significant bleeding or procedures but carry risks of alloimmunization and refractoriness with repeated exposure, among other adverse events [3,14,15]. Antifibrinolytics (eg, tranexamic acid) are useful adjuncts for mucocutaneous bleeding and dental/surgical prophylaxis [11]. Although desmopressin has limited utility in BSS given the primary defect in glycoprotein 1b-mediated adhesion, a modest hemostatic benefit may be achieved in select procedural contexts as an adjunct to local measures [11]. Increasingly, rFVIIa is being employed when transfusions are contraindicated, unavailable, or ineffective [4,12,13]. Individualized plans that minimize alloimmunization and prioritize patient-reported bleeding outcomes are recommended.

NovoSeven has emerged as a potential adjunctive or alternative therapy in the management of bleeding in BSS. By directly activating thrombin generation on the surface of activated platelets and tissue factor-bearing cells, rFVIIa can promote hemostasis independent of glycoprotein 1b-mediated platelet adhesion [10]. While rFVIIa was originally used off-label in this context, its efficacy was later demonstrated in randomized trials [13]. Its application has since expanded in clinical practice for platelet function disorders and inherited thrombocytopenias [14,15].

Several studies have reported successful use of rFVIIa in managing acute bleeding or perioperative prophylaxis in BSS. However, evidence for long-term prophylactic use remains limited. In this report, we describe 2 siblings with severe BSS who experienced frequent and debilitating bleeding episodes. Both demonstrated a marked clinical improvement following the initiation of prophylactic rFVIIa, with a significant reduction in bleeding frequency and related hospitalizations [12].

Poon et al (2009) reviewed multiple cases of platelet function disorders, including BSS, treated with rFVIIa, reporting a 91% success rate in controlling bleeding episodes [4]. Similarly, Inagaki et al (2006) described a pediatric patient with a qualitative platelet disorder who achieved effective bleeding control with rFVIIa administered perioperatively at a dose of 90 μg/kg every 2 hours [12]. Lusher et al (1994), in a randomized trial evaluating rFVIIa in hemophilia patients with inhibitors, demonstrated significant efficacy in surgical settings, indirectly supporting the hemostatic potential of rFVIIa in non-hemophilia bleeding disorders [13].

Importantly, this case highlights the potential benefits of rFVIIa prophylaxis in patients with a high bleeding burden, particularly those at risk of alloimmunization or refractoriness due to prior transfusions [13]. The treatment was well tolerated in both patients, with no reported adverse effects or thrombotic events. Nevertheless, the long-term safety of rFVIIa prophylaxis in this population has yet to be established.

Our experience aligns with the available case-based literature, suggesting that prophylactic rFVIIa may significantly improve quality of life and reduce healthcare utilization in patients with severe BSS. However, optimal dosing intervals, long-term outcomes, and cost-effectiveness remain inadequately addressed in the current literature and should be investigated through prospective multicenter studies.

Although rFVIIa has demonstrated efficacy in managing bleeding in platelet function disorders, concerns remain regarding its thrombotic safety profile. Thromboembolic events have been reported with rFVIIa use, particularly in off-label settings. O’Connell et al (2006) noted a 4.4% event rate, although no cases were reported in patients with inherited platelet disorders like BSS [14].

The present report contributes to the growing body of anecdotal evidence supporting rFVIIa as an effective prophylactic therapy for BSS. However, the absence of standardized dosing guidelines, the cost of therapy, and the risk of thrombotic complications necessitate further prospective studies to define optimal treatment protocols and assess long-term efficacy and safety.

Conclusions

BSS is a rare but serious inherited platelet disorder that requires lifelong management due to the risk of recurrent and potentially life-threatening bleeding. In this case report, 2 brothers with severe BSS experienced a significant reduction in the frequency of bleeding episodes and hospital admissions following prophylactic treatment with rFVIIa. This outcome highlights the potential role of rFVIIa as an effective alternative to platelet transfusions, particularly in patients with frequent bleeding or transfusion-related complications. While these cases demonstrate promising results, further studies are needed to establish standardized guidelines for the prophylactic use of rFVIIa for BSS, including optimal dosing, duration, and long-term safety.