Acquired Factor VII Deficiency Associated with Bronchogenic Carcinoma: A Case Report
Congenital factor VII (FVII) deficiency is the most common of the rare bleeding disorders with an estimated prevalence of 1:500,000 cases. An isolated acquired FVII deficiency is even less frequent, although acquired FVII deficiency, along with FII, FV, and FX deficiencies, may be commonly identified in situations of vitamin K deficiency (liver disease, malabsorption, anticoagulant therapy with vitamin K antagonists).  An isolated acquired FVII deficiency may be suspected in individuals with a prolongation of prothrombin time (PT), a normal activated partial thromboplastin time (aPTT) and a personal and family history negative for inherited bleeding disorders. The diagnosis of this coagulation defect is then confirmed by the specific evaluation of FVII levels that may be reduced to a variable degree, while other factor levels (e.g., FII, FV, FX) are normal. The concomitant presence, however, in some cases of a lupus anticoagulant (accompanied by a prolonged aPTT) may hinder and delay the correct diagnostic workup. In contrast with the majority of blood coagulation factor deficiencies, both congenital and acquired forms show a weak correlation between clinical manifestations and FVII levels and a great heterogeneity ranging from no or mild symptoms to life-threatening hemorrhages.  Acquired FVII deficiency has been reported in association with several conditions, including infectious diseases (sepsis), malignant disorders (solid tumors, acute leukemia, and lymphoproliferative malignancies), and drugs (antibiotics).   In approximately 15% of cases, no underlying diagnosis was identified. Several possible mechanisms, strictly associated with the underlying disorder, have been suggested to explain acquired FVII deficiency: decreased synthesis, accelerated consumption or catabolism, neutralization by autoantibodies, abnormal adsorption by tumor cells, and synthesis of a qualitatively abnormal hypoactive FVII molecule. Here, we report the case of the management of a patient with an acquired FVII deficiency associated with bronchogenic carcinoma.
A 71-year-old man was admitted on September 2, 2020 to the Lung Unit of the city hospital of Mantova (Italy) due to fever, cough, dysphonia, and evidence at chest radiogram and computed tomography scan of an occluding left bronchial mass. The patient was then scheduled for a rigid bronchoscopy with laser-assisted mechanical resection of the endobronchial mass. At physical examination, skin bruising was present, particularly at the trunk and the limbs. Evaluation of severe acute respiratory syndrome coronavirus 2 by reverse transcription polymerase chain reaction on nasal swab was negative. In the past he had undergone appendectomy and inguinal hernioplasty without hemorrhagic complications. The patient also reported to be affected by a mild familiar deficiency of clotting FXII without any personal or relatives bleeding symptoms. The patient was receiving angiotensin-converting enzyme inhibitor for essential hypertension and acetyl salicylic acid (ASA, 100 mg/day) for an acute coronary syndrome treated with angioplasty 3 years earlier. Preoperative blood exams revealed a mild anemia (hemoglobin 10.5 g/dL) and a prolongation of PT (international normalized ratio 1.41, normal range 0.88–1.12) and aPTT (ratio 1.47, normal range 0.82–1.18) with normal platelet count and fibrinogen level. Liver function tests were normal and the serological screen for hepatitis C virus and hepatitis B virus as well as the search for lupus anticoagulant were negative. The level of clotting factors confirmed the already known deficiency of FXII (36%, normal range 70–120%) and also showed reduced FVII levels (21% in two different blood samples, normal range 50–150%). The other clotting factors (FXI, FIX, FVIII, FX, FV, and FII) were within normal range. ASA was immediately interrupted. On September 8, 2020 the patient underwent rigid bronchoscopy at the University Hospital of Brescia with removal of the neoplastic mass occluding the main left bronchus after laser devascularization. Thirty minutes before the operation, the patient was treated with recombinant activated FVII (rFVIIa, NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) at a prophylactic dose of 20 μg/kg given as an intravenous bolus. A check of FVII 30 minutes after rFVIIa infusion (immediately before bronchoscopy) showed levels of 150%. An effective hemostasis was observed by surgeons during the mass removal with no bleeding complications occurring during or after operation. The histologic report from biopsy confirmed the diagnosis of bronchogenic squamous cell carcinoma. No other doses of rFVIIa were administered. The FVII levels were then monitored daily and ranged between 41 and 47% ([Fig. 1]). No bleeding symptoms were recorded. The patient is currently undergoing a chemoradiotherapy regimen and the last FVII laboratory check (October 5, 2020) was 42%.
Only few cases have been reported in the literature on acquired FVII deficiency associated with bronchogenic carcinoma. After a systematic literature search in PubMed/Medline without temporal or language restrictions another two cases were retrieved.  Interestingly, in the case reported by Campbell et al a FVII inhibitor was detected while in the second case reported by Zili et al no evidence of FVII autoantibody was demonstrated. Also, in our patient, the PT-based mixing study excluded the presence of a FVII inhibitor. In addition, the rapid increase of FVII levels until the lower limit of normality immediately after the removal of a significant amount of the tumor mass was consistent with the pathogenic mechanism involving the FVII adsorption by cancer cells, in the presence of normal plasma levels of the other clotting factors. This patient had moreover a concomitant inherited FXII mild deficiency and the consequent aPTT prolongation contributed to complicate the diagnostic process. As for the case described here, also the patient reported by Zili et al underwent a surgical procedure for lung cancer removal requiring replacement therapy. In that case, prophylaxis with fresh frozen plasma (1 mL/kg) was utilized without hemorrhagic complications. The patient reported here was successfully managed with rFVIIa for endoscopic removal of bronchial lesion.
In conclusion, this case, the third reported so far in literature on acquired FVII deficiency associated with lung cancer, allows us to make two considerations: first, since cancer is one of the most frequent causes of acquired coagulation disorders,  it is advisable to perform a first level coagulation screening (i.e., PT and aPTT) in all patients with neoplasms at diagnosis, including bronchogenic carcinomas which show an increasing frequency, especially in the presence of hemorrhagic diathesis. Second, patients with acquired FVII deficiency can be safely and effectively managed with rFVIIa for bleeding treatment or prophylaxis for surgeries and invasive procedures, especially in cases without high titer autoantibody detection, in which a first line treatment with activated prothrombin complex concentrate is recommended.
12. Juli 2021 (online)
© 2021. Thieme. All rights reserved.
Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA
- 1 Sevenet PO, Kaczor DA, Depasse F. Factor VII deficiency: from basics to clinical laboratory diagnosis and patient management. Clin Appl Thromb Hemost 2017; 23 (07) 703-710
- 2 Mulliez SM, Devreese KM. Isolated acquired factor VII deficiency: review of the literature. Acta Clin Belg 2016; 71 (02) 63-70
- 3 Girolami A, Santarossa C, Cosi E, Ferrari S, Lombardi AM. Acquired isolated FVII deficiency: an underestimated and potentially important laboratory finding. Clin Appl Thromb Hemost 2016; 22 (08) 705-711
- 4 La Pecorella M, Mariani G. For International Registry on Congenital Factor VII Deficiency. Factor VII deficiency: defining the clinical picture and optimizing therapeutic options. Haemophilia 2008; 14: 170-1175
- 5 Delmer A, Horellou MH, Andreu G. et al. Life-threatening intracranial bleeding associated with the presence of an antifactor VII autoantibody. Blood 1989; 74 (01) 229-232
- 6 Aguilar C, Lucía JF, Hernández P. A case of an inhibitor autoantibody to coagulation factor VII. Haemophilia 2003; 9 (01) 119-120
- 7 Anoun S, Lamchahab M, Oukkache B, Qachouh M, Benchekroun S, Quessar A. Acquired factor VII deficiency associated with acute myeloid leukemia. Blood Coagul Fibrinolysis 2015; 26 (03) 331-333
- 8 Campbell E, Sanal S, Mattson J. et al. Factor VII inhibitor. Am J Med 1980; 68 (06) 962-964
- 9 Zili M, Hammami S, Marghli A. et al. Deficit acquis, isole en facteur VII et cancer bronchique. A propos d'un cas. Tunis Med 2005; 83 (06) 363-365
- 10 Franchini M, Castaman G, Coppola A. et al; AICE Working Group. Acquired inhibitors of clotting factors: AICE recommendations for diagnosis and management. Blood Transfus 2015; 13 (03) 498-513