Hemostatic rescue with rFVIIa in Bernard–Soulier syndrome refractory to HLA-matched platelet transfusion

Abstract

We report the case of a man in his 50’s diagnosed with Bernard-Soulier syndrome (BSS) in childhood who developed refractory gluteal bleeding following a fall accident. The patient underwent four hematoma evacuation procedures and multiple platelet transfusions, including HLA (human leukocyte antigen) -matched platelet concentrates, without achieving sustained hemostatic control. Given the lack of response to platelet transfusion and ongoing bleeding risk, Eptacog Alfa (recombinant activated factor VII; rFVIIa) was administered for 4 days, following the dosing regimen recommended for Glanzmann thrombasthenia in surgical bleeding settings. Hemostasis was achieved shortly after rFVIIa administration, and no further surgical evacuation was necessary. Importantly, no thromboembolic complications occurred despite the use of rFVIIa. This case demonstrates that rFVIIa can serve as an effective adjunctive hemostatic therapy in patients with BSS who are refractory to platelet transfusions. We reviewed the existing literature on rFVIIa use in patients with BSS and summarized the clinical contexts, dosing strategies, efficacy, and safety outcomes. Our experience suggests that early consideration of rFVIIa may help prevent repeated surgical interventions and reduce bleeding-related morbidity in complex cases.

Introduction

Bernard-Soulier syndrome (BSS) is a rare congenital platelet adhesion disorder characterized by macrothrombocytopenia and impaired platelet adhesion due to defects in the glycoprotein Ib-IX-V complex on the platelet surface, leading to reduced binding of von Willebrand factor and defective initial platelet tethering to the subendothelium [1, 2]. Clinically, BSS manifests with bleeding diathesis, ranging from mucocutaneous bleeding, epistaxis, gingival bleeding, menorrhagia, to trauma or surgery‐related hemorrhage.

Standard management includes platelet transfusion, antifibrinolytic agents, and desmopressin. However, platelet transfusion can be ineffective in some cases due to alloimmunization (development of anti-HLA (human leukocyte antigen) or anti-platelet glycoprotein antibodies) or platelet refractoriness, rendering hemostatic control particularly challenging. In such settings, adjunctive hemostatic strategies, such as antifibrinolytics (e.g., tranexamic acid and ε-aminocaproic acid) and procoagulant factor therapies, may be considered [1–5].

One such adjunct is recombinant activated factor VII (rFVIIa; eptacog alfa), which enhances thrombin generation on activated platelet surfaces and may partially bypass the requirement for normal platelet adhesion and aggregation. The therapeutic rationale is that in patients with platelet adhesion defects, the augmentation of local thrombin generation can stabilize the hemostatic plug despite impaired platelet function [1–9]. Although the literature on rFVIIa use in patients with BSS is limited, existing reports are encouraging. Most evidence comes from isolated case reports or small series, and no standardized dosing protocols have been established. Moreover, concerns regarding potential thromboembolic complications persist when rFVIIa is used off-label. Consequently, additional case-based evidence is crucial for refining the clinical approach to this therapy.

Here, we describe the case of a middle-aged man with BSS diagnosed in childhood who developed a traumatic gluteal hematoma requiring four hematoma evacuations and repeated platelet transfusions, including HLA-matched platelets, without achieving hemostatic success. Administration of rFVIIa over a 4-day period resulted in definitive hemostasis and eliminated the need for further surgical intervention. We discuss this case in the context of prior reports and highlight practical considerations regarding the use of rFVIIa in BSS, including indications, dosing, timing, adjunctive measures, and safety.

Case report

A man in his 50’s with a long-standing diagnosis of BSS was admitted following a low-energy fall accident that resulted in a large gluteal hematoma. BSS was diagnosed at age 4 years, characterized by macrothrombocytopenia and absent ristocetin-induced platelet agglutination, with deficiency of the glycoprotein Ib-IX complex confirmed by flow cytometry. He has had recurrent mucocutaneous bleeding episodes since 4 years of age, and has received more than 200 units of platelet transfusions at our institution over the past 10 years, without any history of major surgical procedures.

Platelet antibody testing revealed the presence of anti-HLA antibodies; therefore, HLA-matched platelet transfusions were administered whenever feasible, with advence preparation.

On presentation, the patient exhibited painful swelling in the right gluteal region. Imaging revealed a large subgluteal hematoma in the right gluteus muscle. The initial management consisted of hematoma evacuation and transfusion of standard platelet concentrates (10 units) administered immediately before and during surgery. Despite transfusion, the platelet count increased only transiently, and recurrent bleeding necessitated repeated evacuations. Over the following 2 weeks, four surgical evacuations were performed, each preceded by platelet transfusion. Because of persistently poor platelet count increments and recurrent bleeding, HLA-matched platelet transfusions (10 units) were subsequently administered but failed to achieve hemostasis.

Given the refractoriness to platelet therapy and the ongoing risk of further bleeding, adjunctive therapy with rFVIIa was initiated. The dosing regimen was selected according to protocols established in randomized clinical trials of rFVIIa in hemophilia, and some case reports of BSS [9–15]. rFVIIa was administered at a dose of 90 µg/kg every 2 h on day 1 (12 doses), every 3 h on day 2 (8 doses), every 3 h on day 3 (8 doses), and every 3 h on day 4 (4 doses) for a total of 32 doses over 4 days. Concurrently, tranexamic acid (0.25 g every 8 h) was administered to provide adjunctive antifibrinolytic support while minimizing the potential risk of thrombotic complications, particularly in the setting of concomitant rFVIIa administration, and platelet transfusions were withheld unless clinically necessary. After the first two doses of rFVIIa, the bleeding output markedly decreased. Following the full 4-day course, there was no further hematoma expansion or recurrent bleeding, and no additional surgical intervention was required.

The platelet count remained low (10–50 × 10⁹/L) but stable throughout the treatment. The patient had no history of venous or arterial thrombosis and no comorbidities known to significantly increase the risk of thrombosis. Thrombotic complications were closely monitored by serial D-dimer measurements, which never exceeded 3 μg/mL, and no evidence of thrombosis was detected. He was discharged on postoperative day 27 (on hospital day 42) with stable hemoglobin levels (Fig. 1) and no recurrent bleeding at the 3-month follow-up.

Fig. 1.

Dynamics of hemoglobin and platelet count levels. Abbreviations: Plt: platelet, Hb: hemoglobin, rFVIIa: recombinant activated factor VII, PC: platelet concentrate, HLA; human leukocyte antigen

Histological examination of the evacuated hematoma demonstrated organized clot formation without vascular malformation (Fig. 2). The decision to discontinue further platelet transfusions after rFVIIa therapy was based on a previously poor transfusion response and the potential risk of alloimmunization. However, given the severity of bleeding and the patient’s extensive transfusion history, HLA-matched platelet transfusions were continued as supportive therapy when available to maximize any residual platelet contribution, while rFVIIa served as the primary hemostatic agent.

Fig. 2.

Intraoperative findings. Preoperative (A), Intraoperative (B), Postoperative (C). Excised hematoma specimen (D)

Discussion

Here, we describe a man in his 50’s with BSS who developed a major gluteal hematoma refractory to repeated platelet transfusions despite HLA-matched concentrates and achieved hemostasis with a 4-day course of rFVIIa (eptacog alfa). To our knowledge, while rFVIIa use in BSS has been reported, our case is noteworthy for the adult age, repeated surgical hematoma evacuations, documented platelet refractoriness, and successful avoidance of further surgery via rFVIIa.

Previous studies support the use of rFVIIa in patients with BSS (Table 1). For example, Yüksel et al. reported a case of severe gastrointestinal bleeding in BSS with factor VII replacement [11]. Ozelo et al. reported successful control of severe hemorrhages with rFVIIa (≈ 90–122 µg/kg) in two patients (three bleeding episodes) after failure of conventional therapies, including platelets and antifibrinolytics [12]. Hacihanefioglu et al. described two further patients treated prophylactically/therapeutically with rFVIIa [13]. Tefre et al. reported that siblings undergoing surgery were successfully managed with rFVIIa [14]. Boppana et al. reported a perioperative case in a 17-year-old adolescent in whom rFVIIa was used because of platelet transfusion failure [15].

Table 1.

Reported cases of rFVIIa use in BSS

No.	Reference	Patient characteristics	Clinical setting	rFVIIa dose & schedule	Outcome
1	Yüksel O et al., Dig Dis Sci. 2004;49(5):885–7 [11]	39-year-old female with BSS	Severe recurrent gastrointestinal bleeding	Dose not precisely stated (for 5 days)	Hemostasis achieved after surgery; no thrombosis
2	Ozelo MC et al., Ann Hematol. 2005;84(12):816–822 [12]	Two sisters (15 and 24 years) with congenital BSS	Severe epistaxis and menorrhagia	~ 90–122 µg/kg IV boluses (2–3 doses per episode)	Hemostasis achieved; no thrombosis
3	Hacihanefioglu A et al., Thromb Res. 2007;120(3):455–457 [13]	Two related patients (28 and 30 years) with confirmed BSS	(1) Gastrointestinal bleeding (2) Menorrhagia + Tooth extraction	90 µg/kg pre-/peri-procedurally; repeated q2–3 h as needed	Effective control; no thromboembolic events
4	Tefre KL et al., Haemophilia. 2009;15(1):281–284 [14]	Two brothers (children/adolescents) with BSS	(1) Knee and eye surgery (2) Dental extraction and Gastrointestinal bleeding	90 µg/kg q3–4 h perioperatively	Successful surgical hemostasis; uneventful recovery
5	Boppana S et al., J Med Cases. 2018;9(2):44–46 [15]	17-year-old female with BSS	Perioperative bleeding	1 mg (~ 15 µg/kg) repeated every 2–3 h intraoperatively	Hemostasis achieved; no thrombosis reported
6	Present case (Okamoto et al., 2025)	50-year-old male with BSS (HLA-matched platelet transfusion refractory)	Recurrent gluteal hematoma requiring four surgical evacuations	90 µg/kg q2h (Day 1) → q3h (Day 2,3,4); 32 total doses	Definitive hemostasis; no further surgery; no thrombosis

These cases suggest that rFVIIa may serve as an effective adjunctive hemostatic agent in patients with BSS, especially when platelet transfusion is insufficient.

Mechanistically, in BSS, the platelet adhesive defect leads to inadequate initial platelet plug formation. rFVIIa works by binding to the exposed tissue factor and directly activating factor X on activated platelets, thereby boosting thrombin generation and stabilizing fibrin formation, even when platelet-mediated adhesion is impaired. This may compensate for platelet dysfunction in patients with BSS and support hemostasis [6–8]. Key practical considerations from the literature and our case include the early identification of platelet transfusion refractoriness, timely initiation of rFVIIa rather than after multiple failed interventions, and concurrent use of antifibrinolytics.

In our case, the prolonged period of repeated hematoma evacuations and platelet transfusions (4 surgical events) illustrates how delayed use of rFVIIa may result in increased morbidity. We propose that in patients with BSS who demonstrate poor response to platelets (e.g., due to alloimmunization or platelet refractoriness) and present with major bleeding or surgery risk, early adjunctive rFVIIa should be considered.

Nevertheless, caution is warranted: rFVIIa is off-label in BSS, dosing is not standardized, and the risk of thromboembolism must be monitored. A review of prior cases did not report major thrombotic events, but the number of cases was small [9–15]. Furthermore, the cost and resource implications are considerable.

From a publication perspective, our case adds to the literature by extending the adult age range, demonstrating successful use in repeated surgical hematoma settings, and affirming that rFVIIa may salvage hemostasis where HLA‐matched platelets have failed. Future directions include the need for consensus on dosing guidelines, registry data collection, and perhaps a comparison of prophylactic versus therapeutic rFVIIa use in BSS [16].

In conclusion, this case supports the role of rFVIIa as a hemostatic adjunct in patients with BSS and platelet transfusion refractoriness. In cases of clinically significant bleeding refractory to standard therapy, early multidisciplinary consideration of rFVIIa may reduce surgical morbidity and improve outcomes.

Author contributions

YO wrote the manuscript. YO, SI, SS, and CM were involved in the clinical management of the patient. KY, NM and AT supervised this study. All authors have given their final approval of the manuscript.

Funding

This research was supported by FY2025 Kyoto University Hospital Research Fund for Young Scientists.

Data availability

The data supporting the findings of this study are available from the corresponding author upon reasonable request.

Declarations

Ethical approval

The administration of recombinant activated factor VII (rFVIIa) in this patient with Bernard–Soulier syndrome was an off-label intervention performed under emergency circumstances, as conventional hemostatic therapies had failed to achieve bleeding control. Due to the urgent nature of the situation, formal approval from the institutional review board (IRB) was not obtained prior to treatment. However, the patient was fully informed of the off-label use, potential risks, and anticipated benefits, and provided written informed consent for the treatment. The management was conducted in accordance with the ethical principles outlined in the Declaration of Helsinki.

Patient consent for publication

Informed consent was obtained from the patient for publication of this case report.

Competing interests

The authors declare no competing interests.