Recurrent Vital Thrombotic Events in a Young Man with FVIII Gene Duplication
The coagulation system is a highly complex regulatory mechanism in the human body, essential for maintaining hemostasis and preventing excessive bleeding. However, abnormalities in this system can lead to thrombotic events, which can be life-threatening. This case report describes a young man who experienced recurrent vital thrombotic events, including cerebral venous sinus thrombosis (CVST), coronary thrombosis, and left ventricular thrombus, in the absence of typical hypercoagulable risk factors or protein deficiencies. Genetic testing revealed a rare duplication of the FVIII gene, which may have contributed to his thrombotic episodes.
Case Presentation
The patient was a 24-year-old man with a history of CVST three years prior, for which he was treated with warfarin (3 mg/day) for one year. At the time of the initial CVST diagnosis, he had no identifiable risk factors for atherosclerosis or a family history of coronary heart disease or recurrent thrombosis. He presented to the emergency room with intermittent chest pain lasting 11 days and severe, oppressive chest pain persisting for 11 hours. An electrocardiogram (ECG) revealed ST-segment elevation in leads I, aVL, and V1–V6, indicative of myocardial infarction (MI). His blood pressure was 145/78 mmHg, and his heart rate was 118 beats per minute. Physical examination revealed no cardiac murmurs, crackles, or wheezes in the lung bases.
Emergency coronary angiography demonstrated incomplete obstruction of the left anterior descending (LAD) artery with a thrombus extending distally. Thrombus aspiration therapy was performed, resulting in reperfusion of the LAD. Optical coherence tomography (OCT) confirmed the presence of a massive red thrombus, although the arterial wall appeared normal with a clearly visible three-layered architecture. Echocardiography revealed decreased motion of the left ventricular apex but no mural thrombus or intracardiac shunt.
A comprehensive thrombophilia screen was performed, including tests for activated protein C resistance, antithrombin III, protein S, anticardiolipin antibodies, lupus anticoagulant, and fibrinogen. All results were within normal ranges: antithrombin III was 95% (normal range 80%–120%), activated fibrinolysin was 95% (normal range 80%–150%), activated protein C was 91% (normal range 70%–140%), and protein S was 82% (normal range 63.5%–149%). A hematological system panel genetic test was also conducted.
The patient was treated with a continuous infusion of the platelet IIb/IIIa inhibitor tirofiban (0.125 μg·kg−1·min−1) for 24 hours, followed by low-molecular-weight heparin (Clexane 6000 U every 12 hours) for four days. His chest pain resolved, and the ECG showed ST-segment resolution. Secondary prevention measures included dual antiplatelet therapy, an angiotensin-converting enzyme inhibitor (ACEI), a beta-blocker, and a statin. Folate was added due to hyperhomocysteinemia. Anticoagulant therapy was not initiated initially, as no evidence of hypercoagulability was found.
Four weeks after the MI, echocardiography revealed a left ventricular mural thrombus, despite the absence of left ventricular wall motion abnormalities. Warfarin (3 mg/day) was added to the dual antiplatelet therapy. Prior to starting warfarin, coagulation factor levels were assessed, revealing a slight elevation in coagulation factor VIII (FVIII) activity to 166% (normal range 100%–150%). Other coagulation factors were within normal limits. Genetic testing identified a duplication of the chrX:153991029-154348425 region, which includes the entire FVIII gene (GenBank: NM_000132.4). Two months later, echocardiography showed that the mural thrombus had resolved. The patient continued dual antiplatelet and warfarin therapy for six months, followed by aspirin and warfarin for five months, with no recurrent thrombotic events.
Discussion
The patient’s initial diagnosis of CVST at the age of 21 years was unusual, as CVST is a rare thrombotic event with an annual incidence of 3 to 4 cases per million individuals. It is more commonly observed in young women, particularly during pregnancy or the postpartum period, or in individuals with acquired or congenital prothrombotic conditions such as infection. The European Stroke Organization guidelines recommend oral anticoagulation for 3 to 12 months following CVST.
FVIII is a glycoprotein that plays a critical role in the intrinsic pathway of blood coagulation. Elevated FVIII levels are considered an independent risk factor for venous thrombosis and are frequently observed in patients with CVST. The etiology of persistently elevated FVIII levels remains poorly understood, although inherited factors may play a role in some cases. In this patient, the duplication of the FVIII gene region, which is not currently documented in the Database of Genomic Variants, may have contributed to the elevation in FVIII activity. Such genetic alterations could affect the production, activity, or metabolism of FVIII, thereby influencing hemostasis and coagulation. Further research is needed to elucidate the mechanisms underlying these effects.
Recent studies have also highlighted the importance of genetic testing in patients with thrombotic events. For example, JAK2V617F-positive essential thrombocythemia patients with CVST are more likely to experience recurrent thrombosis. Genetic testing may therefore play a role in risk stratification and management decisions for patients with CVST and other thrombotic conditions.
Conclusion
This case report describes a rare instance of recurrent vital thrombotic events in a young man with a duplication of the FVIII gene. The patient’s history of CVST, coronary thrombosis, and left ventricular thrombus, in the absence of typical hypercoagulable risk factors, underscores the importance of considering genetic abnormalities in the evaluation of thrombotic events. The slight elevation in FVIII activity and the identification of a rare FVIII gene duplication suggest a potential link between genetic alterations and thrombotic risk. Coagulopathy should be carefully evaluated in patients with unexplained thrombotic events, and genetic studies may provide valuable insights into risk stratification and management strategies.
doi.org/10.1097/CM9.0000000000001230
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