Acquired factor V inhibitors are considered to be relatively rare, with a worldwide incidence of three cases each year . They occur spontaneously in patients with no underlying diseases or in association with various diseases or conditions including drug exposure (β-lactam, streptomycin, ceftriaxone, amino glycoside antibiotics and more recently valproic acid ), transfusion of blood products, factor V deficiency after replacement therapy, infections including HIV, tuberculosis and sepsis, postliver or hematopoietic stem cell transplantation, amyloidosis, autoimmune disorders, malignant diseases, and major surgery, especially following exposure to fibrin sealant. The clinical presentation is highly variable ranging from asymptomatic to life-threatening bleeding manifestations . A new case of factor V inhibitor in a patient with squamous cell carcinoma (SCC) of the esophagus is reported.
An 82-year-old man with epistaxis, hematuria, and melena was admitted to our emergency ward. The medical history revealed a solid food dysphagia for the past 6 months. A barium swallow that was conducted 2 months prior to the recent admission showed a filling defect and a narrowing in the middle part of esophagus, but no further evaluation or follow-up was done for him. There was no history suggestive of a long-standing bleeding disorder. Primary laboratory findings revealed hemoglobin (Hb) 106 g/l, platelet count 373 × 103/μl, activated partial thromboplastin time (aPTT; Cephen; Hyphen Biomed, Cergy, France) more than 90 s, and International Normalized Ratio (INR) more than 5 (Biolabo, Maizy, France). In the emergency ward, fresh frozen plasma (FFP), vitamin K, and packed red blood cells were prescribed. These led to cessation of epistaxis and active gastrointestinal bleeding after 48 h, but hematuria persisted and Hb became 83 g/l. The prothrombin time and aPTT did not significantly change and remained prolonged after being mixed with pooled normal plasma in a 1 : 1 ratio. After receiving another 2 units of packed red cells, his Hb increased to 104 g/l and remained above 100 throughout his admission. Being suspicious of the presence of autoantibodies, prednisolone started to be used, with a dose of 60 mg/day. The patient's sample was obtained and sent to a specialized coagulation laboratory for complementary coagulation assay.
Specific coagulation factor activities were determined by the reagents and instruments from Diagnostica (Stago Asnières sur Seine, France), with the following results: PT/INR 5.61, aPTT 90.1 s (reference range: 26–35), mixed aPTT 66.3 s, fibrinogen 224 mg/dl, factor II 69%, factor V 2%, factor VII 19%, factor X 62%, factor VIII 94%, factor IX 62%, factor XI 40%, and factor XII 48%. Factor V, XI, and VII were repeated by diluting the patient's sample with buffer in five different concentrations from 1/20 to 1/300, which showed a return to near normal levels of factor VII (50% by using dilution 1 : 100) and factor XI (60% at 1/200 dilution), but no significant change for factor V. Bethesda inhibitor assay yielded a result of 12 BU for factor V and none for factor X, VII, and XI. The lupus anticoagulant screening tests [kaolin clotting time, PTT-LA, and dilute or modified Russell Viper Venom Test (dRVVT)] showed a possible lupus anticoagulant. Lupus anticoagulant confirmatory tests by dRVVT and by Staclot-LA showed positive results. Additional testing showed nonspecific presence of anticardiolipin (ACL) IgG (35 GPL/ml; Aesku.Diagnostics, Wendelsheim, Germany) and IgM (2.4 GPL/ml; Aesku.Diagnostics) and negative results for anti-β2GP1 IgG (1.1 GAU/ml; Diagnostica Stago) and IgM (4 MAU/ml; Diagnostica Stago). An upper gastrointestinal endoscopy and histopathologic examinations revealed an infiltrative SCC located 22–26 cm from the upper incisor teeth. After 1 week of prednisolone therapy and few applications of radiotherapy, hematuria was ceased totally and after 2 more weeks, screening coagulation tests became normal: PT/INR 1.4, and PTT 38 s (reference range: 25–43). From then on, progressive thrombocytopenia (platelet count: 15 × 103/μl), most probably due to radiotherapy appeared; the patient then became lethargic, febrile, and finally died.
Acquired inhibitors against factor V rarely develop the first case being reported back in 1955. Between 1955 and 2004, about 150 cases were reported  and since then roughly 22 more cases have been reported in the literature. Markedly prolonged aPTT and PT and failure of normal plasma to correct these tests are suggestive of factor V inhibitors .
Malignant diseases, in general, could induce the generation of autoantibodies against a wide range of autoantigens . Malignancy is usually mentioned as an underlying disease associated with coagulation factor V inhibitors . Among 105 cases with factor V inhibitor, malignancies have been noted in 16% of the patients . In another survey, of 33 patients with factor V inhibitor, malignancies were present in 9% of the patients . The underlying malignancies that are recorded in the literature are listed below.
- Multiple myeloma 
- Non-Hodgkin's lymphoma 
- Central nervous system tumors 
- Hepatocellular carcinoma [9,10,16]
- Anaplastic carcinoma 
- Metastatic liver carcinoma 
- Buccal epidermal carcinoma 
- Colon carcinoma [13–15]
- Prostatic carcinoma [6,14]
- Lung cancer (SCC) 
- Pancreatic cancer 
- Ovarian carcinoma 
- Gingival squamous cell carcinoma (associated with tuberculosis) .
In the report of Okita et al., a case of factor V inhibitor is reported in a patient after surgery for esophageal cancer, in which, surgery could be shown as the cause of inhibitor production as the patient had no evidence of any inhibitor at admission. To our knowledge, our patient is the first case in which esophageal SCC has caused factor V inhibitor without any other risk factors such as surgery involved.
The presence of antiphospholipid antibodies has been reported in a large variety of patients with malignancy. About 54% of the patients with solid tumors had positive lupus anticoagulant test results, 41% had elevated ACL IgG, and 64% had elevated ACL IgM titer . The concurrent presence of a lupus anticoagulant has been reported in some cases with acquired factor V inhibitor . Most patients with factor V inhibitor show positive results in confirmatory tests for lupus anticoagulant, particularly if platelet lysates are used in confirmatory tests (platelet neutralization procedure). Favaloro et al. found definite or probable positive lupus anticoagulant results in the majority of their cases and discussed that the specificity and significance of a positive lupus anticoagulant test result is not clear due to the potential interference of factor V inhibitor in the clot-based tests. In our case, the positive lupus anticoagulant test in conjunction with factor V inhibitor may indicate either a true association between the relevant antibodies or just a false one. However, the latter is most likely, because ACL and anti-β2GP1 antibodies gave nonsignificant (less than 40 GPL units) or negative results, respectively.
There is a wide range of bleeding presentations among the patients with acquired factor V inhibitor. The urinary tract, surgical wound, and gastrointestinal tract are the most common sites of bleeding . Some cases have more than one bleeding presentation. In our case, the patient presented with hematuria, epistaxis, and gastrointestinal bleeding. The site of esophageal tumor could be the source of gastrointestinal bleeding.
In patients with factor V inhibitors, treatment of acute bleeding episode is difficult. As no factor V concentrates are available for replacement therapy, for acute hemorrhagic complications various treatment measures including administration of FFP, platelet concentrates, and prothrombin complex concentrate  may be considered. FFP is frequently given, but often ineffectively . The bleeding complications of our patient were clinically improved by FFP transfusion, but hematuria still persisted. Administration of recombinant activated factor VII is also recommended if clinically indicated [22,23]. For reduction and elimination of factor V inhibitor, several methods including prescription of steroids, cytotoxic therapy, intravenous immunoglobulins, and plasmapheresis have been used [3,4]. Streiff and Ness  reviewed the treatment of patients with symptomatic factor V inhibitor and have recommended steroid therapy as an initial trial for those with mild-to-moderate bleeding because of the higher efficiency of corticosteroids with 74% success. Some authors recommended that steroid therapy should be considered as an initial trial for factor V inhibitor in patients who are also suffering from malignancy . In our case, corticosteroid was administered in order to stop persisting hematuria and to eliminate factor V inhibitor. After 1 week of steroid therapy together with radiotherapy, the hematuria ceased and finally after 2 more weeks, PT and PTT returned to normal values.
The authors are most grateful to Professor P.M. Mannucci for valuable advice and comments.
Conflicts of interest
There are no conflicts of interest.
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