Summary of thrombotic events
| Hemophilia subtype and inhibitor status . | Dosing regimen . | Other treatments . | Last AT activity level before the event . | Medical history . | Thrombotic event . | Description of the event . |
|---|---|---|---|---|---|---|
| Patient with Hemophilia A without inhibitor | Original dose regimen | Concomitant use of factor concentrate in excess of the current bleed management guidelines | 15.9% | Hepatitis C positive, cholecystitis, and smoking history (10 cigarettes a day). No history of drug or alcohol abuse. The family history included a fatal ICH in a male sibling with hemophilia at the age of 2 months. | CVST occurred in 2017∗ | The participant was initially suspected of having viral meningitis but was subsequently diagnosed with subarachnoid hemorrhage on the basis of CT imaging. The participant’s clinical course deteriorated despite the administration of FVIII concentrate 2-3 times a day and the participant died secondary to cerebral edema. After this event, the participant’s CT scans were reviewed, and it was confirmed that the initiating event was a CVST, not a subarachnoid hemorrhage. As a result, the assessment of causality was changed from not related to possibility related to fitusiran. |
| Patient with hemophilia B with inhibitor | Original dose regimen | Concomitant use of BPA (rFVIIa) in excess of the current bleed management guidelines in fitusiran clinical studies | 11.7% | The participant developed an inhibitor to FIX as an infant with the first few exposures to FIX concentrates. Coincident with the development of the FIX inhibitor the participant manifested with anaphylaxis. He had a prolonged attempt of desensitization to FIX along with immunosuppression, but this culminated in the development of nephrotic syndrome, so this was abandoned. Before the initiation of fitusiran, the participant had almost continuous bleeding into his left elbow and most of the bleeds occurred with the use of an arm sling or splint over weeks at a time despite attempts at intensified dosing and prophylaxis. | Atrial thrombosis detected in 2019 | The participant was evaluated by general surgery due to right lower quadrant discomfort. A CT scan confirmed a right atrial mass. Fitusiran dosing was interrupted, and the patient was started on FXa inhibitors. The mass did not change in size during treatment with anticoagulation and the participant began to bleed again under FXa inhibitors. The participant resumed fitusiran and continued to be dosed at 80 mg QM until the program wide hold in 2020, and restarted under 50 mg Q2M with the AT-based dose regimen. A follow-up echocardiogram showed enlargement of the right atrial mass. The event was assessed by the investigator as related to fitusiran, which was subsequently permanently discontinued. |
| Hemophilia subtype and inhibitor status . | Dosing regimen . | Other treatments . | Last AT activity level before the event . | Medical history . | Thrombotic event . | Description of the event . |
|---|---|---|---|---|---|---|
| Patient with Hemophilia A without inhibitor | Original dose regimen | Concomitant use of factor concentrate in excess of the current bleed management guidelines | 15.9% | Hepatitis C positive, cholecystitis, and smoking history (10 cigarettes a day). No history of drug or alcohol abuse. The family history included a fatal ICH in a male sibling with hemophilia at the age of 2 months. | CVST occurred in 2017∗ | The participant was initially suspected of having viral meningitis but was subsequently diagnosed with subarachnoid hemorrhage on the basis of CT imaging. The participant’s clinical course deteriorated despite the administration of FVIII concentrate 2-3 times a day and the participant died secondary to cerebral edema. After this event, the participant’s CT scans were reviewed, and it was confirmed that the initiating event was a CVST, not a subarachnoid hemorrhage. As a result, the assessment of causality was changed from not related to possibility related to fitusiran. |
| Patient with hemophilia B with inhibitor | Original dose regimen | Concomitant use of BPA (rFVIIa) in excess of the current bleed management guidelines in fitusiran clinical studies | 11.7% | The participant developed an inhibitor to FIX as an infant with the first few exposures to FIX concentrates. Coincident with the development of the FIX inhibitor the participant manifested with anaphylaxis. He had a prolonged attempt of desensitization to FIX along with immunosuppression, but this culminated in the development of nephrotic syndrome, so this was abandoned. Before the initiation of fitusiran, the participant had almost continuous bleeding into his left elbow and most of the bleeds occurred with the use of an arm sling or splint over weeks at a time despite attempts at intensified dosing and prophylaxis. | Atrial thrombosis detected in 2019 | The participant was evaluated by general surgery due to right lower quadrant discomfort. A CT scan confirmed a right atrial mass. Fitusiran dosing was interrupted, and the patient was started on FXa inhibitors. The mass did not change in size during treatment with anticoagulation and the participant began to bleed again under FXa inhibitors. The participant resumed fitusiran and continued to be dosed at 80 mg QM until the program wide hold in 2020, and restarted under 50 mg Q2M with the AT-based dose regimen. A follow-up echocardiogram showed enlargement of the right atrial mass. The event was assessed by the investigator as related to fitusiran, which was subsequently permanently discontinued. |
CT, computed tomography; ICH, intracranial hemorrhage.
As assessed by an independent adjudication committee including review of the patient’s CT scans by 3 independent neuroradiologists, who all confirmed that the initiating event was a CSVT and not a subarachnoid hemorrhage.