Factor VII (FVII) deficiency is one of the rare inherited bleeding disorders. Thrombosis has been occasionally described in inherited FVII deficiency. Here, we report a young female with undiagnosed FVII deficiency who presented with cerebral venous sinus thrombosis (CVST). Oral contraceptive pill was found to be prothrombotic risk factor. The CVSToccurred in spite of the congenital FVII deficiency indicating that no definitive antithrombotic protection is assured by this defect. Low molecular weight heparin and anti-Xa assay were found to be safe choice of anticoagulation and monitoring, respectively, in this patien

Adil, Salman Naseem

Qadir, Hira

Rashid, Anila

English

eCommons@AKU

eCommons@AKUDepartment of Pathology and Laboratory Medicine Medical College, PakistanSeptember 2017Cerebral venous sinus thrombosis in a patient withundiagnosed factor VII deficiencyHira QadirAga Khan UniversityAnila RashidAga Khan University, anila.rashid@aku.eduSalman Naseem AdilAga Khan University, salman.adil@aku.eduFollow this and additional works at: https://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiolPart of the Hematology Commons, and the Microbiology CommonsRecommended CitationQadir, H., Rashid, A., Adil, S. N. (2017). Cerebral venous sinus thrombosis in a patient with undiagnosed factor VII deficiency. Journalof the College of Physicians and Surgeons Pakistan, 27(9), S86-S88.Available at: https://ecommons.aku.edu/pakistan_fhs_mc_pathol_microbiol/783S86 Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (Special Supplement 2 of Case Reports): S86-S88INTRODUCTIONInherited factor VII (FVII) deficiency is one of the rareinherited bleeding disorders, with an approximateprevalence of about 1 in 500,000 in its severe form, toone in 350 in the heterozygous state.1,2 In Pakistan,inherited FVII deficiency is one of the commonest rarebleeding disorders, in part, due to traditional consan-guineous marriages.3Factor VII deficiency presents with a wide clinical hetero-geneity characterized by poor correlation of factor levelwith bleeding.4 Clinical features are variable rangingfrom mild or even asymptomatic forms to lethal cerebralhemorrhages. Paradoxically, besides bleeding FVIIdeficiency is also associated with thrombosis. Bothvenous and arterial thrombosis has been reported inapproximately 3 to 4 percent of patients with FVIIdeficiency.5 Most of these have been reported after theuse of factor replacement therapy or coexisting inheritedor other acquired thrombotic risk factors.6 In rare cases,FVII-deficient patients present with spontaneousthrombosis as well.Here, we report a case of FVII deficiency and cerebralvenous sinus thrombosis (CVST) and a review ofmanagement of such cases.CASE REPORTIn September 2015, a 40-year female (gravidity 0, parity 0)with no known comorbids, presented to emergency withcomplaints of jerky movements in the left arm andheadache for three days. Her past history wasunremarkable apart from irregular menstrual cycleswithout menorrhagia for which she was taking tabletnorethisterone, 5 mg, thrice daily for 21 days everymonth for past three months. There was no family orpersonal history of abnormal bleeding. Examinationrevealed decreased power of left upper limb only.Contrast enhanced computerized tomography (CT) scanof brain, done as a part of initial workup of abnormal limbmovement and headache, showed deep CVST involvingall sinuses more marked on the right side extending intothe right internal jugular vein without intracranialhaemorrhage or infarct (Figure 1).Other routine laboratory workup showed haemoglobin13 g/dl (normal: 11.1 - 14.5 g/dl), white blood cell count14 x 109/L (normal: 4 - 1 0 x 109/L), platelets 337 x 109/L(normal: 150 - 400 x 109/L) and no abnormality detectedCASE REPORTCerebral Venous Sinus Thrombosis in a Patient with Undiagnosed Factor VII DeficiencyHira Qadir, Anila Rashid and Salman Naseem AdilABSTRACTFactor VII (FVII) deficiency is one of the rare inherited bleeding disorders. Thrombosis has been occasionally describedin inherited FVII deficiency. Here, we report a young female with undiagnosed FVII deficiency who presented with cerebralvenous sinus thrombosis (CVST). Oral contraceptive pill was found to be prothrombotic risk factor. The CVST occurred inspite of the congenital FVII deficiency indicating that no definitive antithrombotic protection is assured by this defect. Lowmolecular weight heparin and anti-Xa assay were found to be safe choice of anticoagulation and monitoring, respectively,in this patient.Key Words: Factor VII.   Thrombosis.   Cerebral venous sinus.Section of Hematology, Department of Pathology and LaboratoryMedicine, The Aga Khan University Hospital, Karachi.Correspondence: Dr. Anila Rashid, Section of Hematology,Department of Pathology and Laboratory Medicine, The AgaKhan University Hospital, Stadium Road, Karachi-74800.E-mail: anila.rashid@aku.eduReceived: July 16, 2016;   Accepted: March 08, 2017.Figure 1: Sagittal view of skull showing filling defect (thrombus) involving alldeep cerebral venous sinuses.on peripheral smear. Coagulation studies revealedprothrombin time (PT) 27 seconds (sec) (control9-14 sec), INR 2.6 (control ratio ≤ 1) and activated partialthromboplastin time (APTT) 25 sec (control 25-35 sec).Liver function and renal profile was normal. ANA andanti-DNA tests were negative. Anticardiolipin IgM was2.26 MPL unit/ml (normal range ≤ 7 MPL unit /ml). Inview of incidental finding of prolonged PT in the absenceof bleeding symptoms, PT mixing study was ordered thatshowed correction of PT with normal plasma (immediateand after incubation at 37°C for 2 hours) and agedserum. Subsequently, FVII level was checked andfound to be 14%. The findings were suggestive of FVIIdeficiency.Heritable thrombophilia workup was also performed andshowed normal protein S: 85% (60-110%), protein C:89% (normal: 72-160%), antithrombin III: 92% (normal:80-120%) and activated protein C resistance: 0.92(normal: 0.86-1.1 ratio). Homocysteine levels werefound to be 12µmol/L (normal: 5 -12 µmol/L).For CVST, the patient was started on subcutaneousinjections of low molecular weight heparin (LMWH)Enoxaparin, 60mg, twice daily to which she respondedwell with improvement of presenting symptoms.Anticoagulation was monitored clinically and with anti-Xa assay. No FVII levels were repeated during follow-ups as there were no bleeding symptoms at all. Duringhospital stay and subsequent follow-ups in anticoagulationclinic, she remained well with normalization of left armmovement. Until the follow-up in December 2015, nobleeding was reported and anti-Xa remained intherapeutic range. The patient gave her informedconsent prior to inclusion in the study.DISCUSSIONA thrombotic manifestation in a patient congenitally pre-disposed to bleeding always represents an exceptionalevent. To date, occurrence of thromboembolic events inFVII-deficient patients have been reported in severalindividual cases and few case series; and in most ofthese cases, thrombosis was related to replacementtherapies, surgical interventions, and delivery orheritable thrombophilia factors.7,8 In this case, an oralcontraceptive pill was considered to be an associatedthrombotic risk factor. The workup for heritable,thrombophilia was found to be normal. However,prothrombin gene and factor V Leiden mutation couldnot be performed because our facility lacks this capacity.Therefore, the possibility of additional prothrombotic riskfactors cannot be entirely excluded.The type of underlying mutation of FVII like Arg294Valand Arg304Gln are also reported to be associated withthrombotic event.9 In our case, amino acid sequencingand nucleic acid sequencing could not be performed dueto non-availability of these tests at our setup.In a study conducted by Mariani et al., thrombosis in FVIIdeficient patient was not associated with any specificphenotype, mutation zygosity or any specific factor levelcut-off.8 Hence, the exact cause of thrombosis in factorVII deficient patients still remains unclear.International consensus guidelines for treatmentmodalities of the thromboembolic events in rare bleedingdisorders are lacking. In addition, sparse information isfound in literature related to the clinical management ofthrombosis in inherited FVII deficiency. Arellano-Rodrigoet al. reported two cases highlighting the difficulty inmanagement, where one of the patients experiencedmucosal bleeding. Both the patients received warfarin asinitial anticoagulation therapy.10 Use of LMWH byKlovaite et al. for a FVII deficient patient with vena portathrombosis was also associated with bleeding.7 On theother hand, LMWH was found to be safe anticoagulationalternative in our patient. However, optimal doses andsafety remain to be defined. In the same way, the safetyprofile of new direct oral anticoagulants needs to beinvestigated for treating thrombosis in rare bleedingdisorders.To conclude, we have reported the concomitantoccurrence of CVST and a hemorrhagic disorder. Thiscase supports previous observations and demonstratesthat a risk of thrombosis should be considered in thepresence of inherited FVII deficiency. However, thechoice of anticoagulant treatment and prophylaxis needsto be defined.REFERENCES1. Mannucci PM, Duga S, Peyvandi F. Recessively inheritedcoagulation disorders. Blood 2004; 104:1243-52.2. Hunault M, Bauer KA. Recombinant factor VIIa for thetreatment of congenital factor VII deficiency. Semin ThrombHemost 2000; 26:401-5.3. Borhany M, Shamsi T, Naz A, Khan A, Parveen K, Ansari S, et al.Congenital bleeding disorders in Karachi, Pakistan. Clin ApplThromb Hemost 2011; 17:E131-7.4. Mariani G, Dolce A, Marchetti G, Bernardi F. Clinical pictureand management of congenital factor VII deficiency. Haemophilia2004; 4:180-3.5. Ruiz-Saez A. Occurrence of thrombosis in rare bleedingdisorders. Semin Thromb Hemost. 2013; 39:684-92.6. Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore S, Girolami B.Arterial and venous thrombosis in rare congenitalbleeding disorders: a critical review. Haemophilia 2006; 12:345-51.7. Klovaite J, Friis-Hansen L, Larsen FS, Toffner-Clausen N,Bjerrum OW. Vena porta thrombosis in patient with inheritedfactor VII deficiency. Blood Coagul Fibrinolysis 2010; 21:285-8.Cerebral venous sinus thrombosis in a patient with undiagnosed factor VII deficiency Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (Special Supplement 2 of Case Reports): S86-S88 S87Hira Qadir, Anila Rashid and Salman Naseem AdilS88 Journal of the College of Physicians and Surgeons Pakistan 2017, Vol. 27 (Special Supplement 2 of Case Reports): S86-S888. Mariani G, Herrmann FH, Schulman S, Batorova A, Wulff K,Etro D, et al. Thrombosis in inherited factor VII deficiency.J Thromb Haemost 2003; 1:2153-8.9. Girolami A, Candeo N, Bonamigo E, Fabris F. Arg 304 Gln(FVII Padua) and Ala 294 Val mutations are equally present inpatients with FVII deficiency and thrombosis. Eur J Haematol2011; 87:92-4.10. Arellano-Rodrigo E, Gironella M, Nicolau I, Vila M. Clinicalmanagement of thrombosis in inherited factor VII deficiency:a description of two cases. Thromb Haemost 2009; 101:402-4.

Cerebral venous sinus thrombosis in a patient with undiagnosed factor VII deficiency

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Cerebral venous sinus thrombosis in a patient with undiagnosed factor VII deficiency

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