Presentation Details
| Genomic Variations in Factor VII deficiency predisposing to thrombophilia: A case of sinus venous thrombosis in a patient with Factor VII deficiency Aaron C.Lobo 1, Paridhi Ghai1, Fabricio M Webber1, David H.Witt2. 1Bridgeport Hospital/Yale New Haven Health, Bridgeport, CT, USA.2Yale Smilow Cancer Center/Yale school of Medicine, Trumbull, CT, USA |
Abstract
Background: Congenital Factor VII (FVII) deficiency is the most frequently occurring rare inherited bleeding disorder and has a wide spectrum of clinical manifestations ranging from asymptomatic to life-threatening hemorrhage. This heterogenous presentation is influenced by FVII gene polymorphisms and results in poor correlation between FVII activity levels, antigen levels and the bleeding phenotype. A subset of patients with FVII deficiency have been known to present with thrombotic manifestations even in patients with a prior history of severe bleeding. Several genetic variants have been implicated to have thrombogenic pathogenicity, with varying potential mutational mechanisms causing thrombosis. Objectives: This case describes a patient with multiple thrombotic episodes in the setting of FVII deficiency who was subsequently identified to have a two potential prothrombogenic FVII genetic mutations. Results: A 72 year old male diagnosed with Factor VII(FVII) deficiency with prior history of deep vein thrombosis in the setting of perioperative FVII replacement, presented to the hospital with unprovoked altered sensorium and right sided facial droop. Magnetic Resonance Imaging of the brain and venous sinuses was notable for straight vein, internal cerebral veins, and vein of Galen thrombosis with multiple bilateral thalamic, white matter and left caudate ischemic strokes in the setting of a venous thrombosis. He was initiated on a heparin drip and admitted to the intensive care unit for close neurologic monitoring and subsequently transitioned to enoxaparin on discharge. A workup consisting of age appropriate malignancy screening, inherited thrombophilia and JAK2 mutation were negative except presence of a positive plasminogen activation inhibitor -1 deficiency. An extended genomic assessment showed two single nucleotide variations leading to missense mutations: A354V/A294V mutation (autosomal recessive, likely pathogenic ) and V312M mutation (autosomal recessive, of unknown significance). FVII A354V/A294V gene variant present in the serine protease domain, has been frequently described in FVII deficient patients in both homozygous and heterozygous inheritance .This gene and its variants likely exert their influence by altering FVII interaction with FVII activators, substrates and cofactor . This resultant dysfunctional FVII, impairs activated FVII- Tissue Factor interactions without affecting the serine protease features possibly contributing its coagulopathic effects, but also resulting in clinical bleeding. FVII V312M is associated with a milder bleeding phenotype and is usually present as a heterozygous allele with coinheritance of an additional FVII gene variants. Conclusion: Factor VII deficiency with genetic variations that are thrombogenic, predisposes patients to clot. This can occur in the setting of hospitalizations, surgery, and treatment with factor replacement. In this case, the patient’s prothrombotic state was likely brought about by compound heterozygous FVII gene mutations with thrombogenic potential and presence of concomitant plasminogen activation inhibitor-1 (PAI-1) deficiency.
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No part of this publication may be reproduced, distributed, or transmitted in any form or by any means, including photocopying, recording, or other electronic or mechanical methods, without the prior written permission of the author.