- Email: [email protected]
A Rare Complication of Acquired Factor VIII Inhibitors in a Postoperative Oral Cancer Patient: A Case Report
1989
CHEN ET AL
There have been other nonulcerated CPLAs of similar presentation reported in the literature.7-9 In 1998 Manganaro8 discussed a patient having a nonulcerated lesion for years that would change in size. On the basis of its behavior and clinical presentation, it was consistent with a mucous retention phenomenon (MRP). The patient stated that she did bite it often, but it never ulcerated. In the case report of Manganaro, the lesion was determined to be a CPLA on histologic examination. The distance of the artery to the mucosal surface could not be quantified because a wedge resection was not performed. This particular CPLA may have had a depth adequate to avoid ischemic changes to the overlying mucosa. In our patient we could not include an MRP as part of the differential diagnosis for several reasons. First, he stated that the lesion never changed in size over the years. Second, the pulsatile nature of the lesion with an increase clinically after exercise would rule out an MRP and even a mucocele. Lovas and Goodday9 in 1993 stated that the mucosal surface had not ulcerated in one of their cases and that this presentation was attributed to the CPLA being calcified from medial calcific stenosis, thereby preventing a pressure necrosis to the overlying mucosa. The CPLA presented here showed no calcifications histologically in the segment of artery obtained.
It is vital for clinicians to be aware of the presentation of this type of lower lip lesion and to attain a detailed history and include the CPLA as part of the differential diagnosis. When performing an excisional biopsy, the clinician must be prepared for ligation of a brisk arterial bleed even if squamous cell carcinoma is suspected. This report displays a simple technique for dissecting the artery from the submucosa and ligation with silk suture.
References 1. Gallard T: Miliary aneurysm of the stomach giving cause to fatal hematemesis. Bull Soc Med Paris 1, 1884 2. Howell JB, Freeman RG: Prominent inferior labial artery. Arch Dermatol 107:386, 1973 3. Howell JB, Freeman RG: The potential peril from caliber-persistent arteries of the lips. J Am Acad Dermatol 46:256, 2002 4. Miko TL, Adler P, Endes P: Simulated cancer of the lower lip attributed to a “caliber persistent” artery. J Oral Pathol 9:137, 1980 5. Marshall RJ, Leppard BJ: Ulceration of the lip associated with a “calibre-persistent artery.” Br J Dermatol 113:757, 1985 6. Miko TL, Molnar P, Verseckei L: Interrelationship of caliber persistent artery, chronic ulcer and squamous cancer of the lower lip. Histopathology 7:595, 1983 7. Jaspers MT: Oral caliber-persistent artery: Unusual presentations of unusual lesions. Oral Surg Oral Med Oral Pathol 74:631, 1992 8. Manganaro AM: Caliber-persistent artery of the lip: Case report. J Oral Maxillofac Surg 56:895, 1998 9. Lovas JGL, Goodday RHB: Clinical diagnosis of caliber-persistent labial artery of the lower lip. Oral Surg Oral Med Oral Pathol 76:480, 1993 J Oral Maxillofac Surg 68:1989-1993, 2010
A Rare Complication of Acquired Factor VIII Inhibitors in a Postoperative Oral Cancer Patient: A Case Report Ya-Wei Chen, DDS,* Muh-Hwa Yang, MD,† Shou-Yen Kao, DDS, DMSc,‡ and Cheng-Hsien Wu, DDS§ Classical hemophilia is an inherited coagulation disorder due to deficiency of either factor VIII or IX. This is usually associated with bleeding problems from an early age, especially characterized by bleeding into Received from Taipei Veterans General Hospital, Taipei, Taiwan. *Chief Resident, Division of Oral and Maxillofacial Surgery, Department of Stomatology. †Visiting Staff, Division of Hematology-Oncology, Department of Medicine. ‡Chief, Department of Stomatology. §Visiting Staff, Division of Oral and Maxillofacial Surgery, Department of Stomatology.
the joints. In contrast, acquired hemophilia is due to the production of autoantibodies in adult life that inactivate factor VIII. Patients in whom such a coagulopathy develops may present with severe and someAddress correspondence and reprint requests to Dr Wu: Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan; e-mail: [email protected] © 2010 American Association of Oral and Maxillofacial Surgeons
0278-2391/10/6808-0041$36.00/0 doi:10.1016/j.joms.2009.09.007
1990 times catastrophic bleeding episodes, despite having no previous history of a bleeding diathesis. It was reported that approximately 10% of patients with acquired hemophilia have an underlying malignancy.1 On routine laboratory screening, an abnormal isolated prolonged activated partial thromboplastin time (aPTT), along with a normal prothrombin time (PT), thrombin time, and platelet count, is an important feature indicating that physicians should perform further laboratory investigation. We report a rare case of idiopathic, acquired factor VIII inhibitor in a 37-year-old male patient with a history of oral squamous cell carcinoma who had undergone a Commando operation and free-flap reconstruction. The patient had been quite well 1 month before, when he was first admitted to our ward and underwent an operation for squamous cell carcinoma over the right lower buccal gingiva and retromolar trigone. The acquired hemophilia condition was discovered, however, during the clinical course of the patient’s second admission with the initial diagnosis of abscess formation with hematoma lysis over the submental region.
Report of a Case A 37-year-old male patient first presented to the Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan, on June 20, 2007, with a chief complaint of a swelling nodular lesion over his right face for 2 weeks. Before coming to our hospital, the patient had taken some oral antibiotics prescribed at another local dental facility. The patient’s medical history was unremarkable, and no known drug allergy was reported. His family history was significant for breast cancer (in his mother) and nasopharyngeal carcinoma (in his father). Physical examination showed an indurated papillary mass over the patient’s right lower buccal gingiva and retromolar trigone, measuring about 5 ⫻ 4 cm, which also made his right lower face look swollen. Squamous cell carcinoma was proved by incisional biopsy, and a Commando operation was performed on June 28, after a thorough cancer image survey by computed tomography, chest radiography,
COMPLICATION OF FACTOR VIII INHIBITORS whole-body bone scan, and whole-abdomen sonography. Laboratory examination showed a normal hematology and coagulation profile (white blood cell count, 9,100/mm3; hemoglobin level, 14.4 g/dL; platelet count, 285,000/L; PT– international normalized ratio, 0.92; and aPTT, 29.2 seconds [normal range, 23.9-35.5 seconds]). The patient also received a right anterolateral thigh fasciocutaneous and left fibular osteocutaneous double-flap reconstruction for the through-and-through postablative surgical defect over the right lower face. He was admitted to the intensive care unit (ICU) for flap care under sedation and ventilatory support via his tracheostomy and with a mechanical ventilator. During hospitalization in the ICU, a red blood cell transfusion was administered and no transfusion reaction was noted; otherwise, no specific episode of a medical problem was found. After 1 week of care in the ICU, the patient was transferred back to the ordinary ward in generally good physical condition and with a stable wound status. Neither infection signs nor fever was noted. After removal of the tracheostomy tube, the patient was discharged on July 20. During the whole course of hospitalization, he received a single dose of penicillin (3 MU) before surgery and antibiotics postoperatively, with 1.5 g of cefuroxime every 8 hours for 14 days and 400 mg of isepamicin sulfate once a day for 1 week. At the follow-up appointment in our outpatient department on July 27, the patient presented with swelling and redness over the submental area with some bloody and purulent discharge from the cutaneous fistula at the submental flap margin (Fig 1). Abscess formation was suspected; thus incision and drainage were performed. The patient was then admitted to our ward again for wound infection management and further adjuvant concurrent chemoradiation if the wound condition stabilized. Although the wound was treated meticulously by dry-to-wet dressing and intravenous administration of antibiotics (cefazolin and gentamicin), it showed no improvement at all. We decided to perform a debridement operation, and the patient’s laboratory values showed an elevated white blood cell count, at 14,600/mm3; a decreased hematocrit level to 30.9%; and a hemoglobin level of 9.9 g/dL. In addition, an isolated prolonged aPTT (58.6 seconds) was noted with a normal PT– international normalized ratio (0.97). Heparin contamination during the blood extraction procedure was considered at first without further attention at that time. We performed the wound debridement as scheduled on July 31, and the wound over the submental flap margin was closed. Another 2-cm dehiscent wound was found over the oropharyngeal
FIGURE 1. A, The patient received a composite resection and free-flap reconstruction over his right lower face. The arrowhead shows the submental flap margin area where a cutaneous fistula with some bloody and purulent discharge was noted, and the arrow shows the unhealed wound that is detailed in (B). B, Intraoral unhealed wound. Chen et al. Complication of Factor VIII Inhibitors. J Oral Maxillofac Surg 2010.
1991
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FIGURE 2. Changes in aPTT (diamonds) and platelet count (triangles) of the patient during his 2 periods of hospitalization. The response of aPTT to recombinant factor VIII (Kogenate) and recombinant factor VII (NovoSeven) in the last few days of the clinical course should be noted. The days are numbered starting from the day of the patient’s first operation. (AG, aminoglycoside; BT, blood transfusion; Cefa, cefazolin; FFP, fresh-frozen plasma; PCN, penicillin; pRBC; packed red blood cells.) Chen et al. Complication of Factor VIII Inhibitors. J Oral Maxillofac Surg 2010.
flap margin during the operation, and it was repaired with sling sutures. After surgery, the wound condition seemed to be improved; however, bloody discharge from the wound and blood-tinged sputum developed later. No significant finding was noted on chest radiographs, sputum examination, and other laboratory tests. Red blood cell transfusion was performed immediately after we noted a rapid decrease in hemoglobin level (6.8 g/dL). One episode of fever was noted after transfusion without severe complication. To rule out pedicle problems, the patient underwent a second wound debridement and examination on August 6. Empirical antibiotics, cefuroxime and metronidazole, were used after surgery. No obvious bleeder was found either extraorally or intraorally, but a dehiscent wound was again found in the flap margin over the right oropharynx and was resutured. Unfortunately, massive bleeding from the oral cavity developed immediately after surgery and could not be controlled by surgical procedures. The coagulation profile was re-evaluated, and an isolated prolonged aPTT was found (96.2 seconds). Fresh-frozen plasma was transfused, and partial recovery of coagulopathy was noted. Under the impression of acquired coagulopathy, a mixing aPTT study was examined and the result showed that the 1:1 mix of the patient’s serum with control clotting factors reduced the aPTT to 46.7 seconds immediately (0 hours) but yielded a prolonged aPTT, to 86.6 seconds, later (after 2 hours). Disseminated intravascular coagulation tests showed generally normal values: fibrin degradation products, 2.23 g/mL (normal ⬍2.95 g/mL); D-dimer, 0.64 g/mL (normal ⬍2.09 g/mL); and fibrinogen, 441 mg/dL (normal range, 200-400 mg/dL). The previously mentioned data suggested the existence of an acquired clotting factor inhibitor. Further studies examining the intrinsic coagulation factors VIII, IX, XI, and XII and factor inhibitor confirmed the decrease in factor VIII level (1% [normal range, 50%-150%]) with factor VIII inhibitor (12 Bethesda units). The lupus coagulant factor was absent. The patient subsequently received a regimen of recombinant factor VIII (Kogenate-FS F8; Bayer, Tarrytown, NY),
1,000 U every 8 hours for 5 days, and methylprednisolone, 62.5 mg daily, before the recombinant factor VII or activated prothrombin complex concentrate (FEIBA; Baxter AG, Vienna, Austria) was available. The value of aPTT was checked after the treatment but it was still prolonged (71.7 seconds). The Kogenate-FS F8 was then shifted to recombinant factor VII 180,000 IU (NovoSeven; Novo Nordisk, Hillerod, Denmark) every 3 hours. It was tapered over time with a continuous resolution of the bleeding. The regimen was used for the duration of 7 days until the patient’s aPTT was reduced to 33.2 seconds. Fortunately, no other complications occurred, and the serial values of aPTT on the follow-up laboratory examinations were all within normal limits. The clinical course, laboratory test results, and treatment of this case are summarized in Figure 2.
Discussion A thorough medical history, physical examination, and laboratory tests, including aPTT/PT and platelet count, may be used to screen most patients with current bleeding. However, patients without previously mentioned conditions in whom a bleeding problem later develops postoperatively should also be carefully evaluated to ensure good intraoperative hemostasis. Although acquired coagulation disorders are not as common and well known as hemophilia A, hemophilia B, and von Willebrand disease, they might be found unexpectedly in hospitalized patients. An acquired form of coagulation factor deficiency typically presents later in life, with some cases first noted after surgical procedures. It may also cause catastrophic bleeding with significant morbidity and mortality. aPTT evaluates the intrinsic coagulation pathway and is a good tool for screening coagulation disorders.
1992 In a hospitalized patient who is not known to have the hereditary coagulation disorders, the incorrect collection of blood through an indwelling catheter that has been flushed with heparin could be the most common cause of isolated prolonged aPTT. The encountered problem should be confirmed by redrawing a blood sample and avoiding the same error. If the data still show an isolated prolonged aPTT, a mixing study is the most common way to further delineate the causes and should be done as the first survey. Later, a series of laboratory studies should be done to determine the differential diagnosis, such as detection of the levels of some intrinsic factors and the existence of factor inhibitors and lupus anticoagulant. Factor VIII functions as a cofactor to factor IXa in the tenase complex, and a deficiency of factor VIII reduces the generation of thrombin on the surface of activated platelets. The causes of acquired factor VIII inhibitor may be attributed to the development of alloantibodies to factor VIII in patients with congenital hemophilia A undergoing recombinant factor VIII supplementation. Although the majority of patients with acquired hemophilia are labeled idiopathic, possible associated conditions have been reported previously. The most commonly reported conditions associated with the development of circulating anti–factor VIII antibodies are autoimmune disorders (12%-18%) and the postpartum period (10%).2-5 Other conditions include underlying malignancies (10%-12%), drug interactions (3%-6%), and skin disorders such as psoriasis, pemphigus, and epidermolysis bullosa (2%5%).1,3,6-9 In this report the possible causes of the generation of anti–factor VIII antibodies are undetermined. We consider the most probable cause to be drug-induced anti–factor VIII antibodies: the clinical course of prolongation of aPTT is consistent with the use of aminoglycoside (Fig 2). Another possible explanation is uncontrolled infection. Cancer- or transfusion-induced factor VIII inhibitor is not very likely in our patient because he first presented with the bleeding problem 33 days after he underwent the major operation for cancer, and we have only transfused red blood cells when he was under ICU care. Neither transfusion reaction nor any other abnormal clinical conditions were noted. Spontaneous remission of the inhibitor is not uncommon in cases in which the inhibitor is associated with an underlying disorder, once the underlying disease is under control. In idiopathic acquired hemophilia, however, spontaneous recovery is not the rule.10 Treatment strategies of acquired hemophilia can be divided into 2 steps: control of bleeding and elimination of inhibitor. To control bleeding associated with inhibitor, a titer of less than 5 to 10 Bethesda units may have a favorable response by use of factor VIII concentrates. The dose of factor VIII concentrates is empiric, and
COMPLICATION OF FACTOR VIII INHIBITORS
factor VIII activity levels should be carefully monitored throughout the course of therapy. In patients with severe bleeding and an inhibitor, a titer greater than 5 to 10 Bethesda units will immediately neutralize large quantities of factor; thus factor VIII therapy will not be effective in these patients. Bypassing agents with either recombinant human factor VIIa (rVIIa) or activated prothrombin complex concentrates (anti-inhibitor coagulant complex, FEIBA) is prudent.11-17 To date, there is no assay available for monitoring response to FEIBA and rVIIa. However, a dosing regimen of FEIBA of 75 U/kg every 8 to 12 hours to the maximal daily dose of 200 U/kg was shown to yield a good response rate.18 Recombinant VIIa binds to the surface of activated platelets, where it supports thrombin generation, thus bypassing the need for factor VIII. The typical dosing regimen of rVIIa is 90 to 120 g/kg every 3 hours until bleeding is stopped. It should be noted that the maximal dose should not be exceeded, because the risk of thromboembolism has been reported.19 Inhibitor elimination requires the use of various immunosuppressive agents or extracorporeal plasmapheresis. Plasmapheresis is useful in patients with uncontrolled bleeding with high-titer inhibitors who have not responded to bypassing therapy. Steroid therapy (prednisolone, 1 mg/kg per day) is the most popular immunosuppressive agent, with many reported successes, whereas cytotoxic agents (cyclophosphamide, 2 mg/kg per day) played a role as the second-line therapy.20,21 There are also other options for the treatment of acquired factor VIII inhibitors, such as administration of intravenous immune globulin or cyclosporine and target therapy of anti-CD20 monoclonal antibody (rituximab). Further clinical trials are still needed to confirm their efficacy. We treated our patient successfully with recombinant factor VIII combined with corticosteroids and then shifted to recombinant factor VII or activated prothrombin complex concentrate. The bleeding was under control after proper medical treatment; therefore, plasmapheresis and immunosuppressive agents were not applied in our case. This is the first case report on the development of factor VIII inhibitors in an oral cancer patient. The possible causes of postoperative coagulopathy may be use of antibiotics and uncontrolled infection. However, cancer-related factor VIII inhibitor cannot totally be ruled out. Treatment of the postsurgical factor VIII inhibitor including recombinant factor VIII combined with corticosteroids and recombinant factor VII or activated prothrombin complex concentrate. Plasmapheresis or immunosuppressive therapy is necessary when bleeding is uncontrolled. We therefore suggest that a thorough examination of the coagulation profile is mandatory in oral cancer patients receiving
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radical surgery, and factor VIII inhibitor should be considered when uncontrolled bleeding occurs during or after surgery. Timely diagnosis and proper treatment are necessary in these cases.
References 1. Sallah S, Wan JY: Inhibitors against factor VIII in patients with cancer. Analysis of 41 patients. Cancer 91:1067, 2001 2. Shwaiki A, Lara L, Ahmed F, et al: Acquired inhibitor to factor VIII in small cell lung cancer: A case report and review of the literature. Ann Hematol 80:124, 2001 3. Green D, Lechner K: A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 45: 200, 1981 4. Morrison AE, Ludlam CA, Kessler C: Use of porcine factor VIII in the treatment of patients with acquired hemophilia. Blood 81:1513, 1993 5. Hauser I, Schneider B, Lechner K: Post-partum factor VIII inhibitors. A review of the literature with special reference to the value of steroid and immunosuppressive treatment. Thromb Haemost 73:1, 1995 6. Miles BA, Finn RA: Circulating factor VIII inhibitor: Case report and review. J Oral Maxillofac Surg 63:253, 2005 7. Hultin MB: Acquired inhibitors in malignant and nonmalignant disease states. Am J Med 91:9S, 1991 8. Yee TT, Taher A, Pasi KJ, et al: A survey of patients with acquired haemophilia in a haemophilia centre over a 28-year period. Clin Lab Hematol 22:275, 2000 9. Sallah S, Nguyen NP, Abdallah JM, et al: Acquired hemophilia in patients with hematologic malignancies. Arch Pathol Lab Med 124:730, 2000 10. Pintado T, Taswell HF, Bowie EJ: Treatment of life-threatening hemorrhage due to acquired factor VIII inhibitor. Blood 46: 535, 1975
1993 11. Ma AD, Carrizosa D: Acquired factor VIII inhibitors: Pathophysiology and treatment. Hematology Am Soc Hematol Educ Program 432, 2006 12. Franchini M, Gandini G, Di Paolantonio T, et al: Acquired hemophilia A: A concise review. Am J Hematol 80:55, 2005 13. Hay CR, Brown S, Collins PW, et al: The diagnosis and management of factor VIII and IX inhibitors: A guideline from the United Kingdom Haemophilia Centre Doctors Organisation. Br J Haematol 133:591, 2006 14. Collins PW: Treatment of acquired hemophilia A. J Thromb Haemost 5:893, 2007 15. Lusher JM: Recombinant factor VIIa (NovoSeven) in the treatment of internal bleeding in patients with factor VIII and IX inhibitors. Haemostasis 26:124, 1996 (suppl 1) 16. Scharrer I: Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency. Haemophilia 5:253, 1999 17. Liebman HA, Chediak J, Fink KI, et al: Activated recombinant human coagulation factor VII (rFVIIa) therapy for abdominal bleeding in patients with inhibitory antibodies to factor VIII. Am J Hematol 63:109, 2000 18. Sallah S: Treatment of acquired haemophilia with factor eight inhibitor bypassing activity. Haemophilia 10:169, 2004 19. Guillet B, Pinganaud C, Proulle V, et al: Myocardial infarction occurring in a case of acquired haemophilia during the treatment course with recombinant activated factor VII. Thromb Haemost 88:698, 2002 20. Collins PW, Hirsch S, Baglin TP, et al: Acquired hemophilia A in the United Kingdom: A 2-year national surveillance study by the United Kingdom Haemophilia Centre Doctors’ Organisation. Blood 109:1870, 2007 21. 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 70: 753, 1993
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There have been other nonulcerated CPLAs of similar presentation reported in the literature.7-9 In 1998 Manganaro8 discussed a patient having a nonulcerated lesion for years that would change in size. On the basis of its behavior and clinical presentation, it was consistent with a mucous retention phenomenon (MRP). The patient stated that she did bite it often, but it never ulcerated. In the case report of Manganaro, the lesion was determined to be a CPLA on histologic examination. The distance of the artery to the mucosal surface could not be quantified because a wedge resection was not performed. This particular CPLA may have had a depth adequate to avoid ischemic changes to the overlying mucosa. In our patient we could not include an MRP as part of the differential diagnosis for several reasons. First, he stated that the lesion never changed in size over the years. Second, the pulsatile nature of the lesion with an increase clinically after exercise would rule out an MRP and even a mucocele. Lovas and Goodday9 in 1993 stated that the mucosal surface had not ulcerated in one of their cases and that this presentation was attributed to the CPLA being calcified from medial calcific stenosis, thereby preventing a pressure necrosis to the overlying mucosa. The CPLA presented here showed no calcifications histologically in the segment of artery obtained.
It is vital for clinicians to be aware of the presentation of this type of lower lip lesion and to attain a detailed history and include the CPLA as part of the differential diagnosis. When performing an excisional biopsy, the clinician must be prepared for ligation of a brisk arterial bleed even if squamous cell carcinoma is suspected. This report displays a simple technique for dissecting the artery from the submucosa and ligation with silk suture.
References 1. Gallard T: Miliary aneurysm of the stomach giving cause to fatal hematemesis. Bull Soc Med Paris 1, 1884 2. Howell JB, Freeman RG: Prominent inferior labial artery. Arch Dermatol 107:386, 1973 3. Howell JB, Freeman RG: The potential peril from caliber-persistent arteries of the lips. J Am Acad Dermatol 46:256, 2002 4. Miko TL, Adler P, Endes P: Simulated cancer of the lower lip attributed to a “caliber persistent” artery. J Oral Pathol 9:137, 1980 5. Marshall RJ, Leppard BJ: Ulceration of the lip associated with a “calibre-persistent artery.” Br J Dermatol 113:757, 1985 6. Miko TL, Molnar P, Verseckei L: Interrelationship of caliber persistent artery, chronic ulcer and squamous cancer of the lower lip. Histopathology 7:595, 1983 7. Jaspers MT: Oral caliber-persistent artery: Unusual presentations of unusual lesions. Oral Surg Oral Med Oral Pathol 74:631, 1992 8. Manganaro AM: Caliber-persistent artery of the lip: Case report. J Oral Maxillofac Surg 56:895, 1998 9. Lovas JGL, Goodday RHB: Clinical diagnosis of caliber-persistent labial artery of the lower lip. Oral Surg Oral Med Oral Pathol 76:480, 1993 J Oral Maxillofac Surg 68:1989-1993, 2010
A Rare Complication of Acquired Factor VIII Inhibitors in a Postoperative Oral Cancer Patient: A Case Report Ya-Wei Chen, DDS,* Muh-Hwa Yang, MD,† Shou-Yen Kao, DDS, DMSc,‡ and Cheng-Hsien Wu, DDS§ Classical hemophilia is an inherited coagulation disorder due to deficiency of either factor VIII or IX. This is usually associated with bleeding problems from an early age, especially characterized by bleeding into Received from Taipei Veterans General Hospital, Taipei, Taiwan. *Chief Resident, Division of Oral and Maxillofacial Surgery, Department of Stomatology. †Visiting Staff, Division of Hematology-Oncology, Department of Medicine. ‡Chief, Department of Stomatology. §Visiting Staff, Division of Oral and Maxillofacial Surgery, Department of Stomatology.
the joints. In contrast, acquired hemophilia is due to the production of autoantibodies in adult life that inactivate factor VIII. Patients in whom such a coagulopathy develops may present with severe and someAddress correspondence and reprint requests to Dr Wu: Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Veterans General Hospital, No. 201, Section 2, Shih-Pai Road, Taipei 112, Taiwan; e-mail: [email protected] © 2010 American Association of Oral and Maxillofacial Surgeons
0278-2391/10/6808-0041$36.00/0 doi:10.1016/j.joms.2009.09.007
1990 times catastrophic bleeding episodes, despite having no previous history of a bleeding diathesis. It was reported that approximately 10% of patients with acquired hemophilia have an underlying malignancy.1 On routine laboratory screening, an abnormal isolated prolonged activated partial thromboplastin time (aPTT), along with a normal prothrombin time (PT), thrombin time, and platelet count, is an important feature indicating that physicians should perform further laboratory investigation. We report a rare case of idiopathic, acquired factor VIII inhibitor in a 37-year-old male patient with a history of oral squamous cell carcinoma who had undergone a Commando operation and free-flap reconstruction. The patient had been quite well 1 month before, when he was first admitted to our ward and underwent an operation for squamous cell carcinoma over the right lower buccal gingiva and retromolar trigone. The acquired hemophilia condition was discovered, however, during the clinical course of the patient’s second admission with the initial diagnosis of abscess formation with hematoma lysis over the submental region.
Report of a Case A 37-year-old male patient first presented to the Division of Oral and Maxillofacial Surgery, Department of Dentistry, Taipei Veterans General Hospital, Taipei, Taiwan, on June 20, 2007, with a chief complaint of a swelling nodular lesion over his right face for 2 weeks. Before coming to our hospital, the patient had taken some oral antibiotics prescribed at another local dental facility. The patient’s medical history was unremarkable, and no known drug allergy was reported. His family history was significant for breast cancer (in his mother) and nasopharyngeal carcinoma (in his father). Physical examination showed an indurated papillary mass over the patient’s right lower buccal gingiva and retromolar trigone, measuring about 5 ⫻ 4 cm, which also made his right lower face look swollen. Squamous cell carcinoma was proved by incisional biopsy, and a Commando operation was performed on June 28, after a thorough cancer image survey by computed tomography, chest radiography,
COMPLICATION OF FACTOR VIII INHIBITORS whole-body bone scan, and whole-abdomen sonography. Laboratory examination showed a normal hematology and coagulation profile (white blood cell count, 9,100/mm3; hemoglobin level, 14.4 g/dL; platelet count, 285,000/L; PT– international normalized ratio, 0.92; and aPTT, 29.2 seconds [normal range, 23.9-35.5 seconds]). The patient also received a right anterolateral thigh fasciocutaneous and left fibular osteocutaneous double-flap reconstruction for the through-and-through postablative surgical defect over the right lower face. He was admitted to the intensive care unit (ICU) for flap care under sedation and ventilatory support via his tracheostomy and with a mechanical ventilator. During hospitalization in the ICU, a red blood cell transfusion was administered and no transfusion reaction was noted; otherwise, no specific episode of a medical problem was found. After 1 week of care in the ICU, the patient was transferred back to the ordinary ward in generally good physical condition and with a stable wound status. Neither infection signs nor fever was noted. After removal of the tracheostomy tube, the patient was discharged on July 20. During the whole course of hospitalization, he received a single dose of penicillin (3 MU) before surgery and antibiotics postoperatively, with 1.5 g of cefuroxime every 8 hours for 14 days and 400 mg of isepamicin sulfate once a day for 1 week. At the follow-up appointment in our outpatient department on July 27, the patient presented with swelling and redness over the submental area with some bloody and purulent discharge from the cutaneous fistula at the submental flap margin (Fig 1). Abscess formation was suspected; thus incision and drainage were performed. The patient was then admitted to our ward again for wound infection management and further adjuvant concurrent chemoradiation if the wound condition stabilized. Although the wound was treated meticulously by dry-to-wet dressing and intravenous administration of antibiotics (cefazolin and gentamicin), it showed no improvement at all. We decided to perform a debridement operation, and the patient’s laboratory values showed an elevated white blood cell count, at 14,600/mm3; a decreased hematocrit level to 30.9%; and a hemoglobin level of 9.9 g/dL. In addition, an isolated prolonged aPTT (58.6 seconds) was noted with a normal PT– international normalized ratio (0.97). Heparin contamination during the blood extraction procedure was considered at first without further attention at that time. We performed the wound debridement as scheduled on July 31, and the wound over the submental flap margin was closed. Another 2-cm dehiscent wound was found over the oropharyngeal
FIGURE 1. A, The patient received a composite resection and free-flap reconstruction over his right lower face. The arrowhead shows the submental flap margin area where a cutaneous fistula with some bloody and purulent discharge was noted, and the arrow shows the unhealed wound that is detailed in (B). B, Intraoral unhealed wound. Chen et al. Complication of Factor VIII Inhibitors. J Oral Maxillofac Surg 2010.
1991
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FIGURE 2. Changes in aPTT (diamonds) and platelet count (triangles) of the patient during his 2 periods of hospitalization. The response of aPTT to recombinant factor VIII (Kogenate) and recombinant factor VII (NovoSeven) in the last few days of the clinical course should be noted. The days are numbered starting from the day of the patient’s first operation. (AG, aminoglycoside; BT, blood transfusion; Cefa, cefazolin; FFP, fresh-frozen plasma; PCN, penicillin; pRBC; packed red blood cells.) Chen et al. Complication of Factor VIII Inhibitors. J Oral Maxillofac Surg 2010.
flap margin during the operation, and it was repaired with sling sutures. After surgery, the wound condition seemed to be improved; however, bloody discharge from the wound and blood-tinged sputum developed later. No significant finding was noted on chest radiographs, sputum examination, and other laboratory tests. Red blood cell transfusion was performed immediately after we noted a rapid decrease in hemoglobin level (6.8 g/dL). One episode of fever was noted after transfusion without severe complication. To rule out pedicle problems, the patient underwent a second wound debridement and examination on August 6. Empirical antibiotics, cefuroxime and metronidazole, were used after surgery. No obvious bleeder was found either extraorally or intraorally, but a dehiscent wound was again found in the flap margin over the right oropharynx and was resutured. Unfortunately, massive bleeding from the oral cavity developed immediately after surgery and could not be controlled by surgical procedures. The coagulation profile was re-evaluated, and an isolated prolonged aPTT was found (96.2 seconds). Fresh-frozen plasma was transfused, and partial recovery of coagulopathy was noted. Under the impression of acquired coagulopathy, a mixing aPTT study was examined and the result showed that the 1:1 mix of the patient’s serum with control clotting factors reduced the aPTT to 46.7 seconds immediately (0 hours) but yielded a prolonged aPTT, to 86.6 seconds, later (after 2 hours). Disseminated intravascular coagulation tests showed generally normal values: fibrin degradation products, 2.23 g/mL (normal ⬍2.95 g/mL); D-dimer, 0.64 g/mL (normal ⬍2.09 g/mL); and fibrinogen, 441 mg/dL (normal range, 200-400 mg/dL). The previously mentioned data suggested the existence of an acquired clotting factor inhibitor. Further studies examining the intrinsic coagulation factors VIII, IX, XI, and XII and factor inhibitor confirmed the decrease in factor VIII level (1% [normal range, 50%-150%]) with factor VIII inhibitor (12 Bethesda units). The lupus coagulant factor was absent. The patient subsequently received a regimen of recombinant factor VIII (Kogenate-FS F8; Bayer, Tarrytown, NY),
1,000 U every 8 hours for 5 days, and methylprednisolone, 62.5 mg daily, before the recombinant factor VII or activated prothrombin complex concentrate (FEIBA; Baxter AG, Vienna, Austria) was available. The value of aPTT was checked after the treatment but it was still prolonged (71.7 seconds). The Kogenate-FS F8 was then shifted to recombinant factor VII 180,000 IU (NovoSeven; Novo Nordisk, Hillerod, Denmark) every 3 hours. It was tapered over time with a continuous resolution of the bleeding. The regimen was used for the duration of 7 days until the patient’s aPTT was reduced to 33.2 seconds. Fortunately, no other complications occurred, and the serial values of aPTT on the follow-up laboratory examinations were all within normal limits. The clinical course, laboratory test results, and treatment of this case are summarized in Figure 2.
Discussion A thorough medical history, physical examination, and laboratory tests, including aPTT/PT and platelet count, may be used to screen most patients with current bleeding. However, patients without previously mentioned conditions in whom a bleeding problem later develops postoperatively should also be carefully evaluated to ensure good intraoperative hemostasis. Although acquired coagulation disorders are not as common and well known as hemophilia A, hemophilia B, and von Willebrand disease, they might be found unexpectedly in hospitalized patients. An acquired form of coagulation factor deficiency typically presents later in life, with some cases first noted after surgical procedures. It may also cause catastrophic bleeding with significant morbidity and mortality. aPTT evaluates the intrinsic coagulation pathway and is a good tool for screening coagulation disorders.
1992 In a hospitalized patient who is not known to have the hereditary coagulation disorders, the incorrect collection of blood through an indwelling catheter that has been flushed with heparin could be the most common cause of isolated prolonged aPTT. The encountered problem should be confirmed by redrawing a blood sample and avoiding the same error. If the data still show an isolated prolonged aPTT, a mixing study is the most common way to further delineate the causes and should be done as the first survey. Later, a series of laboratory studies should be done to determine the differential diagnosis, such as detection of the levels of some intrinsic factors and the existence of factor inhibitors and lupus anticoagulant. Factor VIII functions as a cofactor to factor IXa in the tenase complex, and a deficiency of factor VIII reduces the generation of thrombin on the surface of activated platelets. The causes of acquired factor VIII inhibitor may be attributed to the development of alloantibodies to factor VIII in patients with congenital hemophilia A undergoing recombinant factor VIII supplementation. Although the majority of patients with acquired hemophilia are labeled idiopathic, possible associated conditions have been reported previously. The most commonly reported conditions associated with the development of circulating anti–factor VIII antibodies are autoimmune disorders (12%-18%) and the postpartum period (10%).2-5 Other conditions include underlying malignancies (10%-12%), drug interactions (3%-6%), and skin disorders such as psoriasis, pemphigus, and epidermolysis bullosa (2%5%).1,3,6-9 In this report the possible causes of the generation of anti–factor VIII antibodies are undetermined. We consider the most probable cause to be drug-induced anti–factor VIII antibodies: the clinical course of prolongation of aPTT is consistent with the use of aminoglycoside (Fig 2). Another possible explanation is uncontrolled infection. Cancer- or transfusion-induced factor VIII inhibitor is not very likely in our patient because he first presented with the bleeding problem 33 days after he underwent the major operation for cancer, and we have only transfused red blood cells when he was under ICU care. Neither transfusion reaction nor any other abnormal clinical conditions were noted. Spontaneous remission of the inhibitor is not uncommon in cases in which the inhibitor is associated with an underlying disorder, once the underlying disease is under control. In idiopathic acquired hemophilia, however, spontaneous recovery is not the rule.10 Treatment strategies of acquired hemophilia can be divided into 2 steps: control of bleeding and elimination of inhibitor. To control bleeding associated with inhibitor, a titer of less than 5 to 10 Bethesda units may have a favorable response by use of factor VIII concentrates. The dose of factor VIII concentrates is empiric, and
COMPLICATION OF FACTOR VIII INHIBITORS
factor VIII activity levels should be carefully monitored throughout the course of therapy. In patients with severe bleeding and an inhibitor, a titer greater than 5 to 10 Bethesda units will immediately neutralize large quantities of factor; thus factor VIII therapy will not be effective in these patients. Bypassing agents with either recombinant human factor VIIa (rVIIa) or activated prothrombin complex concentrates (anti-inhibitor coagulant complex, FEIBA) is prudent.11-17 To date, there is no assay available for monitoring response to FEIBA and rVIIa. However, a dosing regimen of FEIBA of 75 U/kg every 8 to 12 hours to the maximal daily dose of 200 U/kg was shown to yield a good response rate.18 Recombinant VIIa binds to the surface of activated platelets, where it supports thrombin generation, thus bypassing the need for factor VIII. The typical dosing regimen of rVIIa is 90 to 120 g/kg every 3 hours until bleeding is stopped. It should be noted that the maximal dose should not be exceeded, because the risk of thromboembolism has been reported.19 Inhibitor elimination requires the use of various immunosuppressive agents or extracorporeal plasmapheresis. Plasmapheresis is useful in patients with uncontrolled bleeding with high-titer inhibitors who have not responded to bypassing therapy. Steroid therapy (prednisolone, 1 mg/kg per day) is the most popular immunosuppressive agent, with many reported successes, whereas cytotoxic agents (cyclophosphamide, 2 mg/kg per day) played a role as the second-line therapy.20,21 There are also other options for the treatment of acquired factor VIII inhibitors, such as administration of intravenous immune globulin or cyclosporine and target therapy of anti-CD20 monoclonal antibody (rituximab). Further clinical trials are still needed to confirm their efficacy. We treated our patient successfully with recombinant factor VIII combined with corticosteroids and then shifted to recombinant factor VII or activated prothrombin complex concentrate. The bleeding was under control after proper medical treatment; therefore, plasmapheresis and immunosuppressive agents were not applied in our case. This is the first case report on the development of factor VIII inhibitors in an oral cancer patient. The possible causes of postoperative coagulopathy may be use of antibiotics and uncontrolled infection. However, cancer-related factor VIII inhibitor cannot totally be ruled out. Treatment of the postsurgical factor VIII inhibitor including recombinant factor VIII combined with corticosteroids and recombinant factor VII or activated prothrombin complex concentrate. Plasmapheresis or immunosuppressive therapy is necessary when bleeding is uncontrolled. We therefore suggest that a thorough examination of the coagulation profile is mandatory in oral cancer patients receiving
CHEN ET AL
radical surgery, and factor VIII inhibitor should be considered when uncontrolled bleeding occurs during or after surgery. Timely diagnosis and proper treatment are necessary in these cases.
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