Ann Thorac Surg 2006;81:362-364
© 2006 The Society of Thoracic Surgeons
Case report
Presentation and Management of a Stage Ia Lung Cancer Patient With a Paraneoplastic Factor VIII Inhibitor
Brooks T. Laselle, BA
a
,
Lisa N. Boggio, MS, MD
b
,
Matthew G. Blum, MD
c
,
*
a Division of Hematology/Oncology, Chicago, Illinois, USA
b Division of Cardiothoracic Surgery, Northwestern Memorial Hospital, Chicago, Illinois, USA
c Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
Accepted for publication August 19, 2004.
* Address correspondence to Dr Blum, 201 E Huron St, Suite 10-105, Chicago, IL 60611 (Email: mblum{at}nmh.org).
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Abstract
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Acquired inhibitors to clotting factors most commonly involve factor VIII and are associated with autoimmune disease. Factor VIII inhibitors can cause severe spontaneous and iatrogenic bleeding that is difficult to manage. Factor VIII inhibitors are rarely associated with solid tumors and only three cases of adenocarcinoma of the lung have been reported. This report describes the multidisciplinary management of a factor VIII inhibitor-producing stage Ia lung adenocarcinoma that ultimately resulted in complete resectability.
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Introduction
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The development of inhibitors to clotting factors may be idiopathic or associated with several conditions: postpartum, autoimmune disorders, malignancy, allergy, drug reactions [1]. Approximately 10% of patients with acquired hemophilia have an underlying malignancy, most commonly those from the prostate, lung, pancreatic, and hematologic causes [2]. The presentation of a fVIII inhibitor as a paraneoplastic process is rarely reported. Three cases of lung adenocarcinoma and fVIII inhibitor are documented [2–4]. Cancers associated with paraneoplastic fVIII inhibitors are difficult to manage because minor invasive diagnostic and therapeutic procedures may be complicated by severe bleeding. This report describes the presentation and successful management of a patient with stage I lung adenocarcinoma and paraneoplastic fVIII inhibitor.
A 78-year-old man with a history of type 2 diabetes mellitus, hypertension, and cerebral vascular accident was admitted with a 1-month history of bruising in the face, arms, flanks, and thighs (Fig 1). His extremities were grossly swollen with decreased sensation, especially the right thumb and forefinger. Medications included clopidogrel and aspirin. His hematologic labs were notable for a prothrombin time of 14 seconds, a partial thromboplastin time of 92 seconds, a hemoglobin of 7.8 g/dL, and a platelet count of 539,000 cells/µL. A mixing study did not correct his partial thromboplastin time. Inhibitor titers to fVIII are quantified by the Bethesda unit (1 unit inactivates 50% of the fVIII in an equivalent volume of normal plasma) [5]. Measured fVIII level was < 5% with a Bethesda titer of 10 Bethesda unit. A contrast enhanced helical computed tomographic scan revealed a 1.8 x 2.5 cm left upper lobe nodule. Adenocarcinoma was diagnosed by fine needle aspiration. Despite pretreatment with activated prothrombin complex concentrates (FEIBA [Baxter, Deerfield, IL]), the biopsy was complicated by severe ecchymosis and bleeding with a decline in hemoglobin of 2 g/dL (Fig 2). The bleeding was initially controlled by administration of recombinant factor VIIa (NovoSeven [NovoNordisk, Princeton, NJ]). Prednisone 1 mg/kg and cyclophosphamide 50 mg twice daily were started in an attempt to decrease the inhibitor and allow resection. The prednisone was discontinued secondary to severe exacerbation of the patient's diabetes. Cyclophosphamide continued for 3 weeks, but it did not decrease the Bethesda titer. After a second spontaneous bleeding episode, intravenous immune globulin (IVIG) increased the fVIII level to 20%, but it did not change the Bethesda titer. One cycle of chemotherapy with carboplatin area under curve 6 and paclitaxel 100 mg/m2 decreased the inhibitor from 10 Bethesda units to 0.8 Bethesda unit with an increase of the fVIII level to 30%. Three additional cycles resulted in complete disappearance of the inhibitor and normalization of the fVIII level. The patient underwent a lobectomy for a stage Ia adenocarcinoma without complications. Two years after resection the patient is asymptomatic without evidence of recurrent tumor or return of clotting abnormalities.
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Comment
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Patients with factor VIII inhibitors may present with a prolonged partial thromboplastin time or excessive bleeding or bruising [1]. Standard coagulation tests show a normal prothrombin time and bleeding time. The patient's plasma is next mixed with normal plasma. Failure to correct the partial thromboplastin time suggests a clotting factor inhibitor. Additional studies assaying specific intrinsic pathway factors (VIII, IX, XI, XII) will show a low or unmeasurable level of factor VIII. The Bethesda method of dilution is used to quantify inhibitor activity [6]. A decline in the Bethesda titer can be used to evaluate the effectiveness of therapy in eliminating or neutralizing factor VIII inhibitor.
The pathogenesis of fVIII inhibitors in cancer is not well defined, but it is likely to be an autoimmune process. The few reports that studied the nature of the inhibitor found that the inhibitor was a polyclonal immunoglobulin G [4, 7]. In addition, paraneoplastic fVIII inhibitors often respond to treatments that are effective for autoimmune diseases. This suggests an autoimmune response to antigens expressed by tumor that are similar to fVIII.
Control of bleeding in patients with acquired fVIII inhibitors was explored by Boggio and colleagues [5]. Human fVIII or desmopressin infusions are effective only for control of acute bleeds with a Bethesda unit of < 5. Higher inhibitor titers require administration of porcine fVIII, recombinant factor-VIIa, or activated prothrombin complex concentrates [5]. Immune suppression with prednisone reportedly eliminates the inhibitor in 50% of the patients [5]. Cyclophosphamide and cyclosporin have been useful for patients who do not respond to steroids [8]. Before an urgent operation, extra corporal immunoadsorption with Staphylococcal protein A to bind IgG from intravascular and extravascular stores is effective, but it requires special equipment. Intravenous immunoglobin G has been used, but only 10% to 15% of patients respond [5].
In 2001, Sallah [2] studied the disappearance of the inhibitor after treatment of cancer by chemotherapy or surgery. Complete remission of fVIII inhibitor titers occurred more frequently with early-stage cancers, lower titers of inhibitor, and higher fVIII levels. However, in some cases, despite treatment of the cancer, there was no improvement in the inhibitor.
Whether fVIII inhibitors can be followed as a marker for recurrent malignancy is unknown. The patient we describe presented with bleeding and fVIII inhibitor as the initial manifestation of lung cancer. Some studies report fVIII inhibitors presented during recurrence of malignancy but not at the initial presentation [4]. This suggests that fVIII inhibitors may appear at any time during the course of a malignancy; thus these may be poor indices for monitoring recurrence of cancer.
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References
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- Bona RD, Riberio M, Klatsky AU, Panek S, Magnifico M, Rickles FR. Continuous infusion of porcine factor VIII for the treatment of patients with factor VIII inhibitors Hematol 1993;30:32-35.
- Kondo H, Shigekiyo T, Kojima A, Saito S, Saijo N. Acquired factor VIII inhibitor in a patient with adenocarcinoma of the lung Jpn J Clin Oncol 1992;22:49-53.[Abstract/Free Full Text]
- Boggio LN, Green D. Acquired hemophilia Rev Clin Exp Hematol 2001;5.4:389-404.
- Kasper CK, Aledort L, Aronson D, et al. A more uniform measurement of factor VIII inhibitor Thromb Diath Haemorrh 1975;34:612.[Medline]
- de Cataldo F, Baudo F, Redaelli R, Pezzetti L. Acquired factor VIII:C inhibitor (IgG) and positive direct coombs' test (IgM) in a patient with lung carcinoma Scand J Haematol 1984;33:171-176.[Medline]
- Green D, Rademaker AW, Briet E. A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies Thromb Haemost 1993;70:753-757.[Medline]
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Abstract
Introduction
