Factor VII deficiency in major artery occlusion stroke.

Abstract

An 82-year-old woman with known Factor VII (FVII) deficiency and history of atrial fibrillation had presented with sudden onset of vertigo, slurred speech, and left-sided hemiparesis starting 20 minutes ago. Symptoms progressed rapidly to somnolence, left-sided hemianopsia, and horizontal nystagmus to the left side. She scored 12 on National Institutes of Health Stroke Scale (NIHSS). Native CT with CT angiography showed occlusion of the P1 section of right posterior cerebral artery (PCA) (Image 1, Panel A). FVII activity at admission was 8.2% (normal activity 50%-150%), international normalized ratio (INR) of 2.9, activated partial thromboplastin time (aPTT) of 26 seconds (normal values 22–38). Digital subtraction angiography showing occlusion of left PCA proximal (P1) segment (red arrow) (A). Transesophageal echocardiography showing left atrial appendage thrombus (LAA) measuring 14 mm × 10 mm (red delineation) (B). Histologic analysis of extracted thrombus. Macroscopic view, hematoxylin and eosin (H&E) (C). High magnification, H&E showing equal proportion of fibrin and red blood cells (D). Clot from this case—high magnification, staining with Factor VII (FVII) antibody, showing virtually no detectable FVII (E). Control—high magnification, staining with FVII antibody—light brown (F) Due to her history of FVII deficiency she was ineligible to intravenous thrombolysis. Therefore, endovascular thrombectomy (EVT) was performed with complete recanalization of artery, 2 hours and 50 minutes after symptom onset. The extracted clot was analyzed and showed equal proportions of red blood cells (RBC) and fibrin consistent with fresh thrombus, without elements of CD34 positive endothelial cells and virtually no presence of FVII (Image 1, Panel C-F). The following day she scored 5 on NIHSS. The patient harbors compound heterozygosity of F7 gene with splice-site and missense-mutation, c.430 + 1G>A and c.934G>A mutations. Her FVII activity which was regularly monitored during the last five years rarely exceeded values of 30% and was usually under 10% of activity, she was deemed to have moderate FVII deficiency. As a child she experienced nose bleeding one to two times per week with bleeding time up to 30 minutes, although with aging the symptoms showed signs of remission with nose bleeding episodes 5–6 times per year. She experienced non-ST elevation myocardial infarction three years before, without specific intervention. Shortly after, aortic valve replacement was indicated for symptomatic aortic stenosis. Secondary prophylaxis with aspirin had to be discontinued because of several bleeding episodes. One year later she experienced an arterial thrombotic event in the region of the right popliteal artery with incomplete ischemia that necessitated thrombendarterectomy. At the same time a heart-pacemaker was implanted for tachy-bradycardy syndrome. Her CHA2DS2-VAS Score was 7 (age ≥ 75 years, female, hypertension, stroke, vascular disease history) putting her in high stroke risk category. Medications at admission were metoprolol 95 mg BID, torasemide 5 mg QD, simvastatin 20 mg QD, and ginkgo biloba 80 mg TID. We referred her to evaluation regarding left atrial appendage closure procedure with Watchman Device. However, transesophageal echocardiography showed a 14 mm × 10 mm large thrombus in left atrial appendage which is a contraindication for device implantation (Image 1, Panel B). She was discharged with NIHSS of 2 with the recommendation of taking aspirin 50 mg daily, and she recovered well. A congenital FVII deficiency is a rare inherited autosomal recessive bleeding disorder with a prevalence of 1:400 000 in Caucasians.1 FVII deficiency is known by its large clinical heterogeneity, encompassing clinically asymptomatic and severe cases with life-threatening bleedings. Since there is no clear correlation between plasma levels of FVII and hemorrhagic diathesis the individual risk is difficult to predict. Most patients with moderate to severe degree of disease are either homozygotes or compound heterozygotes for mutations, however, patients homozygous for the same mutation do not always express the same phenotype suggesting additional environmental factors and/or another genetic components. About one-third of patients with inherited FVII deficiency remain asymptomatic during their life. In symptomatic patients, epistaxis and other mild mucocutaneous bleeds are the most common complaints, however, 10%-15% of patients exhibit severe bleedings. Initial diagnosis of FVII deficiency is based on discordance between the prolonged PT (INR frequently > 2.0) and the normality of aPTT. Diagnosis is finally confirmed by a FVII assay. Genetic testing is not routinely required for the diagnosis of FVII deficiency. Acquired causes of low FVII are very common and must be excluded prior to making a diagnosis of hereditary FVII deficiency, including vitamin K deficiency, liver dysfunction, warfarin, or disseminated intravascular coagulation (DIC). FVII has the shortest half-life among the coagulation factors; therefore, it can be the only low factor in mild forms of these conditions. Despite the impaired coagulation cascade, up to 4.1% patients with FVII deficiency suffer from thrombotic events.2 In a report from the FVII Deficiency Study Group database, 9 of 514 patients suffered from thrombosis, including one case of arterial thrombotic event. Most of the thromboembolic complications were associated with triggering factors such as immobilization, surgical intervention, and coagulation factor replacement therapy like fresh frozen plasma, prothrombin complex-like concentrate, or plasma-derived FVII concentrate.3 Apparently, FVII deficiency does not seem to offer protection against thrombosis when severe prothrombotic risk factors are present.2, 3 In our patient, we excluded additional hypercoagulable disorders like Faktor V Leiden, prothrombin mutation, protein C or S deficiency, antithrombin deficiency, or antiphospholipid syndrome. Only factor VIII activity was significantly elevated (333%—norm. range 50.0%-149.0%), which is considered a week risk factor for thrombosis and could have contributed to the paradoxical hypercoagulability state in our patient.4 However, since factor VIII is an acute phase reactance, factor levels shortly after a thrombotic event are difficult to interpret. Unfortunately, there exists neither consensus nor guidelines for anticoagulation therapy or antithrombotic prophylaxis for patients harboring FVII deficiency. Some researchers found warfarin treatment plausible in the setting of mild FVII deficiency and atrial fibrillation5 and heparin therapy for venous thrombosis without excessive bleeding has been described.3 Interestingly, patients with severe FVII deficiency (<5%) have impaired thrombus formation under high arterial wall shear rate but normal thrombus formation by low shear rate.6 This finding is consistent with left atrial appendage thrombus found in our patient. Left appendage thrombi that develop in atrial fibrillation consist of red-blood cells (RBC) and fibrin, typical of low-flow venous thrombi and, thus, are very susceptible to anticoagulant regimens.7 Conventional trigger factors for thrombotic event in the setting of inherited FVII deficiency should not be underestimated and therapeutic options should be pursued. Although our patient was further treated with low-dose aspirin (50 mg QD), as already suggested by others, direct oral anticoagulation (DOAC) could theoretically be treatment of choice since they do not directly affect FVII activity and could carry less bleeding risk than vitamin K antagonists.5 none All authors contributed significantly to manuscript. SP, JSM, KM, and GP were involved in manuscript preparation and internal review. ETB conducted mechanical thrombectomy and SW conducted histological analysis.