Successful treatment of ligneous gingivitis with warfarin

Gregg Fine, MD,a Kenneth Bauer MD,b Maha Al-Mohaya, DMD,c and Sook-Bin Woo, DMD, MMSc,d Boston, Massachusetts, and Riyadh, Saudi Arabia
BETH ISRAEL DEACONESS MEDICAL CENTER, RIYADH ARMED FORCES HOSPITAL, BRIGHAM AND WOMENS HOSPITAL, AND HARVARD SCHOOL OF DENTAL MEDICINE

Ligneous gingivitis is a rare condition characterized by inammation and nodular gingival enlargement secondary to brin deposits in the gingival that results from plasminogen deciency. Several therapeutic approaches have been used with limited success. We report a case of a patient with homozygous plasminogen deciency and ligneous gingivitis that was initially refractory to local care and systemic antibiotics, but later improved with the addition of warfarin. (Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:77-80)

Ligneous gingivitis/periodontitis is a rare condition characterized by nodular gingival enlargement with ulceration and periodontal tissue destruction. The condition results from plasminogen deciency that leads to the formation of an amorphous brin-rich amyloid-like substance that accumulates in the lamina propria.1,2 Several therapeutic approaches have been used in attempts to treat ligneous gingivitis, including the use of antibiotics, chlorhexidine rinses, topical cromoglycate, hyaluronidase, mitomycin c, topical heparin, systemic steroids, alpha chymotrypsin, azathioprine, oral contraceptive pills, and gingivectomies. These surgical and medical therapies have met with limited success.3-5 This is a report of a patient with extensive ligneous gingivitis and ligneous cervicitis associated with homozygous plasminogen deciency who was successfully treated with warfarin, chlorhexidine rinses, and antibiotics in addition to regular dental scaling and prophylaxis. CASE REPORT
This is a previously reported case of a 52-year-old woman with a history of ligneous cervicitis and ligneous gingivitis secondary to plasminogen deciency.6 She rst developed gingival involvement at age 13 that recurred despite numer-

Clinical Fellow, Department of Medicine, Hematology/Oncology Division, Beth Israel Deaconess Medical Center. b Professor, Department of Medicine, Hematology/Oncology Division, Beth Israel Deaconess Medical Cente. c Consultant of Oral Medicine, Dental Department, Riyadh Armed Forces Hospital. d Attending Dentist, Brigham and Womens Hospital; Associate Professor, Department of Oral Medicine, Infection, and Immunity, Harvard School of Dental Medicine. Received for publication Jul 3, 2008; returned for revision Jul 30, 2008; accepted for publication Aug 2, 2008. 1079-2104/$ - see front matter 2009 All rights reserved. doi:10.1016/j.tripleo.2008.08.007

ous dental scalings. Her gingivitis continued to progress, causing increased gingival pain and the loss of several teeth because of periodontal disease. Her diagnosis of plasminogen deciency was made at age 46. At the age of 49, she presented to the Division of Oral Medicine and Dentistry at the Brigham and Womens Hospital for further management of her ligneous gingivitis. She had no history of coagulation abnormalities or other inherited thrombotic defects. She had a history of infertility, and was diagnosed with ligneous cervicitis at the age of 39 for which she underwent multiple dilation and curettage procedures, laparoscopies, and colposcopies. At 42, she underwent right ovarian cystectomy for dysmenorrhea and pelvic pain due to an adherent ligneous ovarian cyst. She denied a history of ligneous conjunctivitis or other ophthalmologic defects. Her mother had a history of multiple miscarriages. One brother had ligneous conjunctivitis and ligneous gingivitis and periodontitis resulting in the loss of all of his teeth in his forties. He also suffered a stroke in his mid-forties. She had one sister who was healthy. Her only medications at the time were aspirin and citalopram. She had a history of developing hives with exposure to penicillin and sulfa drugs. Intraoral examination showed multiple tender rm ulcerated nodular growths that extended from the free marginal gingiva to the mandibular sulci (Fig. 1). The associated teeth were not mobile. Radiographically, there was moderate alveolar bone loss adjacent to the gingival masses. Histologic examination of the gingival biopsy disclosed hyperorthokeratosis, epithelial acanthosis, extensive epithelial eosinophilic brin deposition, and focal inammation (Fig. 2). Laboratory evaluation of the patient revealed a plasminogen antigen level of 1.3 mg/dL (reference range 7.5-18.5 mg/dL) and a plasminogen activity level of 12% of normal, consistent with plasminogen deciency. Genetic analysis of the plasminogen gene showed homozygosity for a P285A missense and the following polymorphisms: 238C (847C T in exon 7), intron F-14T G, 238Q (982G A in exon 8), 295F(1018C T in exon 8), 342Q (1159A G in exon 9) and 380Q (1273G A in exon 10). The patient was managed with a combination of surgical excision of the gingival masses, 20 mg doxycycline daily, and

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Fig. 1. Gingival mass involving the buccal peridontium and mucosa of (A) the right and (B) the left mandibular molars.

Fig. 3. Gingival mucosa of the (A) right and (B) left mandible after treatment with warfarin.

remain on anticoagulation indenitely. She continued to have no evidence of tooth mobility or recurrence of her gingival lesion 3.75 years later (Fig. 3).

Fig. 2. Histology showed extensive subepithelial eosinophilic brin deposition (hematoxylin-eosin, original magnication 100).

0.12% chlorhexidine digluconate mouth rinse. Additionally, 1 week after surgery she was started on warfarin 5 mg daily with a target international normalized ratio of 2-3 and was to

DISCUSSION Ligneous gingivitis was rst reported in 1847 and is an unusual form of chronic multifocal gingivitis and destructive periodontal disease.7 It is characterized by thick plaque-like nodular masses on the gingiva. Since the initial report, numerous additional cases have been documented, primarily in the Turkish population.1,2 Ligneous gingivitis is usually associated with severe plasminogen deciency, which causes diminished brinolysis and leads to deposition of brin in the lamina propria. Ligneous gingivitis is seen in approximately one-third of patients with homozygous plasminogen deciency.8,9 Additional clinical manifestations of homozygous or compound heterozygous plasminogen deciency include involvement of the tracheobronchial tree, cervix, vagina, uterus, skin, kidneys, and congenital occlusive hydrocephalus.3,10 Plasminogen deciency results from either decreased expression of plasminogen (hypoplasminogenemia, type I) or expression of a normal amount of dysfunc-

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tional plasminogen protein (dysplasminogenemia, type II). The most common genetic defect found in patients with type I plasminogen deciency is the K19E mutation, which accounted for 34% of mutations in a recent series of 50 patients.9 It is hypothesized that this mutation results in a conformational change that reduces the half-life of the protein and results in decreased plasminogen levels. Other mutations, such as P285A, which was found in our patient, lead to signicantly decreased plasminogen secretion from hepatic cells. Plasminogen is a proenzyme converted by tissue-type plasminogen activator or urokinase-type plasminogen activator into plasmin and facilitates the dissolution of brin clots.11 There have been reports of ligneous gingivitis in patients without plasminogen deciency and in patients taking the antibrinolytic drug tranexamic acid, suggesting that other mechanisms contribute to the formation of this lesion.12,13 The pathophysiology of ligneous gingivitis is unclear. Often it is triggered by minor trauma and is thought to involve brin deposition which plays an important role in hemostasis and wound healing.14 Tissue repair is a highly regulated process that involves inammation, cell proliferation, cell migration, angiogenesis, and extracellular matrix production in which the injured tissue is removed and replaced with normal tissue. Mechanical injury of tissues (skin, mucosa, and others) is followed by exudation of plasma proteins, cleavage of brinogen, and formation of brin. Over time, remodeling occurs and the brin matrix is replaced by granulation tissue. Finally, granulation tissue is replaced by a secondary matrix in which collagenous constituents prevail. Local extracellular brinolysis by plasmin is required for the initial removal of the brinrich matrix as well as for the remodeling of the granulation tissue and completion of wound healing. Impairment of this pathway due to hypoplasminogenemia leads to brin accumulation. Warfarin is a vitamin K antagonist that inhibits the normal biosynthesis of the procoagulant factors II, VII, IX, and X. Treatment with warfarin decreases the generation of thrombin that regulates the conversion of brinogen to brin. It is hypothesized that this decreased conversion decreased brin plaque formation in our patient. It is also hypothesized that systemic antibiotics and antimicrobial rinses helped reduce the chronic infection and associated inammation that led to the formation of brin plaques. Earlier reports have shown excision of the brinous masses, especially if they are large, and use of topical heparin, topical plasmin, or corticosteroids to have little benet in managing patients with ligneous gingivitis associated with type I plasminogen deciency.5 Topical plasminogen and intravenous plasminogen concentrate

replacement have shown benet in ligneous conjunctivitis, but require repeated administration owing to its short half-life and are not commercially available in most countries.15,16 In summary, we have reported the effective treatment of a patient with ligneous gingivitis secondary to hypoplasminogenemia using warfarin, low-dose doxycycline, and chlorhexidine mouth rinse. Although local periodontal care alone may have been responsible for improvement, it had failed before in this patient and has been unsuccessful in other cases reported in the literature. In addition to surgery and management of local inammation with antibiotics and antimicrobial rinses, the addition of warfarin to her regular periodontal regimen made a signicant difference in controlling recurrence of her gingival lesions and may be a reasonable adjunctive treatment for other patients with ligneous gingivitis in association with severe plasminogen deciency.
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16. Heidemann D, Williams GA, Hartzer M, Ohanian A, Citron ME. Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen. Cornea 2003;22:760-2. Reprint requests: Gregg Fine, MD Beth Israel Medical Center 330 Brookline Ave Boston, MA 02215 gne@bidmc.harvard.edu

13. Diamond JP, Chandna A, Williams C, Easty DL, Scully C, Eveson J, Richards A. Tranexamic acidassociated ligneous conjunctivitis with gingival and peritoneal lesions. Br. J Ophthalmol 1991;75:753-4. 14. Kluft C. The brinolytic system and thrombotic tendency. Pathophysiol Thromb Haemost 2003/2004;33:425-9. 15. Schott D, Dempe CE, Beck P, Liermann A, Nohr-Pennert A, Goldner M, et al. Therapy with a puried plasminogen concentrate in an infant with ligneous conjunctivitis and homozygous plasminogen Deciency. N Engl J Med 1998;339: 1679-86.