Intracranial Hemorrhage in a Patient of Hemophilia A with Factor VIII Inhibitors Positive: A Case Report

Abstract

Management of intracranial hemorrhage in a patient with hemophilia A and high-titer inhibitors presents a significant challenge to the neurointensivist. The decision between conservative and surgical approaches involves a delicate risk–benefit balance. While conservative management is costly and carries the risk of sudden deterioration, surgical intervention is often complicated by the high likelihood of rebleeding. We report the successful critical care management of a 50-year-old male with hemophilia A and high-titer factor VIII inhibitors who presented with an acute-on-chronic subdural hematoma. His factor VIII levels were markedly low, and conventional factor VIII replacement therapy was ineffective. The bleeding manifestations and laboratory parameters did not improve with standard treatment. The patient was successfully managed using sequential or combined bypassing agent therapy.

 

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Keywords

hemophilia A - ICH - antihemophilic factors - sequential/combined bypass agent therapy

Introduction

Intracerebral hemorrhage is a challenging condition to treat, especially in hemophiliacs. The risk–benefit ratio that determines the balance between conservative and surgical management is very subtle. Conservative management is associated with the risk of sudden deterioration and is expensive, while surgery is always associated with a risk of rebleeding. Here, we discuss the nuances, clinical challenges, and treatment dilemmas encountered while managing a known case of hemophilia A with high titers of inhibitors, presenting with a left acute-on-chronic subdural hematoma (SDH).

 

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Case Report

A 50-year-old male, a known case of hemophilia A, had received multiple factor VIII (FVIII) therapies in the past for gum bleeding and hemarthrosis. He presented with complaints of dull, aching headache for 2 days, followed by multiple episodes of vomiting and loss of consciousness. His trachea was intubated in view of a low Glasgow Coma Scale (GCS) (E1VtM4). Computed tomography (CT) brain showed a left hemispheric acute-on-chronic SDH ([Fig. 1]), with mass effect and midline shift, indicating impending uncal herniation. In the background of hemophilia and a deranged coagulation profile (activated partial thromboplastin time [aPTT]: 75 seconds, FVIII assay: 20%), immediate correction was initiated prior to decompression and clot evacuation. The patient experienced a deterioration in GCS accompanied by bradycardia, culminating in a cardiac arrest in the intensive care unit (ICU). One cycle of cardiopulmonary resuscitation was initiated immediately and return of spontaneous circulation was achieved. He maintained a GCS of E1VtM4 immediate post-arrest phase. Recombinant activated FVII (rFVIIa), FVIII concentrate, and a tranexamic acid infusion, titrated according to body weight, were administered. As FVIII levels exceeded 70%, the patient underwent decompressive craniectomy with evacuation of the SDH followed by surgical tracheostomy (low GCS, airway protection) after 12 hours of ICU stay under continuous coverage of tranexamic acid, FVIII, and rFVIIa.

Fig. 1 CT of patient showing acute on chronic SDH. CT, computed tomography; SDH, subdural hematoma.

Postoperatively, the patient was shifted back to the ICU. FVIII levels were targeted to be maintained above 80% for the next 3 to 4 days. However, the levels remained consistently low (<1%) and were unresponsive to FVIII therapy. A FVIII inhibitor assay and mixing study was sent, which returned positive, with an inhibitor titer of >5 Bethesda Units (BU).The patient subsequently developed gum bleeding, tracheal bleeding, and oozing from the craniectomy site. Treatment was continued with FVIII concentrate (body weight [kg] × 80 × [(1 − hematocrit) × antibody titer (BU)]), along with local application of tranexamic acid. Bypassing agents—rFVIIa and activated prothrombin complex concentrate (aPCC)—were administered based on body weight.

In view of persistent tracheal oozing, gum bleeding, and failure to wean the patient from the ventilator, various medical therapies were attempted. Prednisone was initiated at a dose of 1 mg/kg body weight,[1] but was subsequently discontinued due to the risk of developing ventilator-associated pneumonia.[2] rFVIIa (NovoSeven) was then administered at a dose of 90 mcg/kg every 2 hours for the first four doses, followed by every 4 hours for six additional doses. However, the tracheal and gingival bleeding remained uncontrolled, and inhibitor titers persisted at >5 BU.

Subsequently, the patient was started on sequential/combined bypassing agent therapy, alternating rFVIIa (90 mcg/kg) and aPCC (50 IU/kg) every 6 hours, continued for a total of 6 days. aPTT was monitored every 6 hours, while complete blood count, FVIII assay, and PT/INR (prothrombin time/international normalized ratio) were assessed on alternate days. The patient was closely monitored for any thromboembolic complications. D-dimer, fibrinogen levels, and electrocardiogram (ECG) were evaluated every 4 days.

After 3 weeks of ICU care, the patient's bleeding manifestations decreased, and he was weaned to a T-piece. Sequential CT scans of the brain showed a reduction in the sulcal SDH and GCS improved to E4VtM5. FVIII assay levels improved to 15%, and inhibitor titers decreased to <2 BU. The patient was subsequently referred for rehabilitation.

 

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Discussion

Spontaneous intracranial hemorrhage (ICH) is an uncommon but serious complication in patients with hemophilia, with an incidence of approximately 2.2 to 7.8% and a reported mortality rate of around 34%.[3] Conservative management with antihemophilic factors (AHFs) can be considered for small-volume hematomas, along with close monitoring. Large hematomas with signs of impending uncal herniation typically require surgical evacuation. In patients with hemophilia A undergoing emergency neurosurgical procedures, FVIII levels should be maintained above 100 IU/dL. To achieve this, a dose of FVIII equivalent to body weight × 100 IU/dL × 0.5 should be administered. However, patients who have received multiple transfusions of FVIII in the past may develop FVIII inhibitors. Following exposure to clotting factor replacement therapy, up to 30% of patients with severe hemophilia A[4] develop immunoglobulin G alloantibodies that bind to functional domains on the FVIII molecule, thereby inhibiting or neutralizing its clotting function. In patients with high-titer inhibitors (>5 BU), acute bleeding episodes cannot be effectively controlled with FVIII. One BU is the amount of inhibitor that neutralizes 50% of FVIII activity in an equal volume of normal pooled plasma over 2 hours at 37°C.[5]

Bypassing agents that circumvent the need for FVIII—such as aPCC and rFVIIa—are used to achieve hemostasis in patients with inhibitors. The presence of an inhibitor generally does not alter the site or frequency of bleeding; however, it significantly impairs bleeding control, as patients no longer respond to standard factor replacement therapy. This increases the risk including ICH, soft tissue or muscle bleeds leading to compartment syndrome, and gastrointestinal hemorrhage which can be life-threatening.

aPCC primarily targets the prothrombinase complex and promotes the conversion of prothrombin to thrombin via factor Xa on a phospholipid surface.[6] In contrast, rFVIIa directly activates sufficient factor X on activated platelet surfaces to restore thrombin generation. rFVIIa is a recombinant product with a relatively short half-life of approximately 2 hours,[7] while aPCC is a plasma-derived product with a half-life ranging from 4 to 7 hours.[8] Notably, aPCC may lead to an anamnestic rise in FVIII levels in approximately 20% of patients, as it contains trace amounts of FVIII.

Neither aPCC nor rFVIIa provides hemostatic efficacy as predictable as factor replacement therapy in patients without inhibitors when used as monotherapy.[9] As a result, we employed sequential or combined bypassing therapy in our patient, with close monitoring for thrombotic complications and disseminated intravascular coagulation (DIC). This should be considered in patients with suboptimal response to a single bypassing agent. Alternating rFVIIa and aPCC every 6 hours has been shown to improve hemostatic efficacy while allowing for a reduced total daily dose of aPCC, thereby potentially lowering thrombotic risk.[10]

Supportive therapies should be continued like physical therapy, nutritional support, and gentle tracheal suctioning (e.g., Foley catheter) to avoid mucosal trauma. Frequent assessment of aPTT, PT/INR, complete blood count, FVIII, D-dimer, fibrinogen, inhibitor titers, and ECG monitoring are essential, as bypassing therapies may rarely lead to ischemic complications. Point-of-care tests (POCTs) such as thromboelastography or rotational thromboelastometry can be valuable tools for real-time assessment of global hemostatic function in critically ill patients with hemophilia and inhibitors. These viscoelastic tests help guide therapy by evaluating clot formation dynamics, stability, fibrinolysis, and may support timely adjustments in bypassing agent dosing while minimizing thrombotic risk. However, the high cost of POCT, combined with the significant financial burden of repeated transfusions of AHF, can pose substantial challenges. Given the complexity of managing such cases, early referral to a specialized center with expertise in hemophilia and inhibitor management is essential.

Other alternative therapies for hemophilia A with inhibitors include factor substitution therapy with Emicizumab and immune tolerance induction. However, their role in acute bleeding is debatable.

 

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Conclusion

ICH in a patient with hemophilia A and inhibitors is a formidable challenge. We successfully used sequential/combined bypassing therapy in a patient with high titer of inhibitors who was actively bleeding and was resistant to single bypassing agents. We recommend monitoring these patients closely for any thrombosis or DIC. Since AHFs are always expensive and not readily available, we recommend routine screening for inhibitors in hemophilia patients undergoing frequent FVIII transfusions and take utmost care in selecting patients for therapy.

 

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Conflict of Interest

None declared.

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Publication History

Article published online:
16 July 2025