Ligneous conjunctivitis secondary to a congenital plasminogen deficiency in a dog

Nancy S. Johnstone McLean Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Daniel A. Ward Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Diane V. H. Hendrix Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Robert L. Donnell Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Marcia R. S. Ilha Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996.

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Abstract

Case Description—A 7-month-old 16.6-kg (36.5-lb) sexually intact female Golden Retriever was evaluated because of progressive severe bilateral membranous conjunctivitis, oral lesions, nasal discharge, and cough.

Clinical Findings—Histologic examination of conjunctival biopsy specimens revealed findings consistent with ligneous conjunctivitis. Circulating plasminogen activity was repeatedly low, and congenital plasminogen deficiency was identified as the underlying cause of the ocular, oral, and respiratory lesions.

Treatment and Outcome—Topical and subconjunctival administrations of fresh frozen plasma (FFP), topical administration of cyclosporine, and oral administration of azathioprine had no effect on the conjunctival membranes. Excision of the membranes followed by intensive treatment with topical applications of heparin, tissue plasminogen activator, corticosteroid, and FFP and IV administration of FFP prevented membrane regrowth. Intravenous administration of FFP increased plasma plasminogen activity to within reference limits, improved respiratory and oral lesions, and resulted in weight gain; discontinuation of this treatment resulted in weight loss, signs of depression, and worsening of lesions. After euthanasia because of disease progression, necropsy findings included mild hydrocephalus; multifocal intestinal hemorrhages; and fibrinous plaques in the oral cavity, nasopharynx, trachea, esophagus, and pericardium. Microscopically, the plaques were composed of fibrin and poorly organized granulation tissue. Fibrin thrombi were present within vessels in the lungs, oral cavity, and trachea.

Clinical Relevance—In dogs, congenital plasminogen deficiency can occur and may be the underlying cause of ligneous conjunctivitis. A combination of surgical and medical treatments may improve conjunctival membranes, and administration of FFP IV appears to be effective in treating nonocular signs of plasminogen deficiency.

Abstract

Case Description—A 7-month-old 16.6-kg (36.5-lb) sexually intact female Golden Retriever was evaluated because of progressive severe bilateral membranous conjunctivitis, oral lesions, nasal discharge, and cough.

Clinical Findings—Histologic examination of conjunctival biopsy specimens revealed findings consistent with ligneous conjunctivitis. Circulating plasminogen activity was repeatedly low, and congenital plasminogen deficiency was identified as the underlying cause of the ocular, oral, and respiratory lesions.

Treatment and Outcome—Topical and subconjunctival administrations of fresh frozen plasma (FFP), topical administration of cyclosporine, and oral administration of azathioprine had no effect on the conjunctival membranes. Excision of the membranes followed by intensive treatment with topical applications of heparin, tissue plasminogen activator, corticosteroid, and FFP and IV administration of FFP prevented membrane regrowth. Intravenous administration of FFP increased plasma plasminogen activity to within reference limits, improved respiratory and oral lesions, and resulted in weight gain; discontinuation of this treatment resulted in weight loss, signs of depression, and worsening of lesions. After euthanasia because of disease progression, necropsy findings included mild hydrocephalus; multifocal intestinal hemorrhages; and fibrinous plaques in the oral cavity, nasopharynx, trachea, esophagus, and pericardium. Microscopically, the plaques were composed of fibrin and poorly organized granulation tissue. Fibrin thrombi were present within vessels in the lungs, oral cavity, and trachea.

Clinical Relevance—In dogs, congenital plasminogen deficiency can occur and may be the underlying cause of ligneous conjunctivitis. A combination of surgical and medical treatments may improve conjunctival membranes, and administration of FFP IV appears to be effective in treating nonocular signs of plasminogen deficiency.

A 7-month-old 16.6-kg (36.5-lb) sexually intact female Golden Retriever was evaluated by the University of Tennessee College of Veterinary Medicine Ophthalmology Service because of chronic conjunctivitis, gingival lesions, and respiratory disease. The clinical signs began at 4.5 weeks of age and had progressed. Histologic examination of conjunctival biopsy specimens, cytologic examination and bacterial culture of conjunctival swabs, serologic evaluation for canine distemper, virus isolation, and routine clinicopathologic analyses failed to establish a diagnosis. Oral and topical administrations of antimicrobials, corticosteroids, and nonsteroidal anti-inflammatory drugs and topical administration of cyclosporine had been ineffective.

The dog was small for its age and thin (body condition score, 2/5). Additional examination findings included thick mucopurulent nasal discharge, large submandibular lymph nodes, and a productive cough. Circular, raised, pink, fleshy, mucosal lesions were detected throughout the oral cavity and nasopharynx, and an ulcer was present on the soft palate. Thoracic auscultation revealed harsh referred upper airway sounds. Ophthalmic examination findings included a thick, mucoid discharge bilaterally; menace responses were present (positive), and pupillary light reflexes were considered normal in both eyes. Palpebral reflexes, ocular motility, and dazzle reflexes in both eyes were also considered normal. Results of a Schirmer tear test were 0 mm/min in the right eye and 15 mm/min in the left eye (reference range, ≥ 15 mm/min), indicative of keratoconjunctivitis sicca in the right eye. The cornea of each eye did not retain fluorescein stain; however, fluorescein adhered to the mucoid discharge that coated the conjunctiva in the right eye. Intraocular pressures in the right and left eyes, measured via applanation tonometry, were 18 and 20 mm Hg, respectively (reference range, 15 to 25 mm Hg). Additionally, the dog had marked bilateral membranous conjunctivitis (Figure 1). In the right eye, the entire palpebral conjunctiva was dramatically thickened and hyperemic. A smooth, gray membrane was located at the temporal aspect of the superior palpebral conjunctiva. Chalky, white deposits suggestive of mineralization were present in the palpebral conjunctiva of the inferior eyelid. The membranes and thickened conjunctiva obscured most of the cornea and prevented thorough intraocular examination. In the left eye, a smooth, pink, pedunculated mass occupied the temporal half of the superior palpebral conjunctiva, and the posterior aspect of the nictitating membrane was thickened and hyperemic with focal, chalky, white deposits. Ocular examination results for the left eye were otherwise normal.

Figure 1—
Figure 1—

Photographs (obtained at different time points) of the ocular and oral lesions and general appearance of a 7-month-old dog that was evaluated because of progressive severe bilateral membranous conjunctivitis, oral lesions, nasal discharge, and cough. A—Photograph of the right eye at the initial examination. Notice the marked membranous conjunctivitis. The entire palpebral conjunctiva is dramatically thickened with focal white chalky deposits in the nasal half of the palpebral conjunctiva of the inferior eyelid. B—Photograph of the left eye at the initial examination. A pedunculated mass occupies the temporal half of the superior palpebral conjunctiva. In addition, the posterior aspect of the nictitating membrane is thick and contains chalky, white deposits. C—Photograph of the oral lesions 20 weeks after the initial examination. Notice the circular, fleshy lesions on the buccal mucosa and the fibrinous material coating the gingiva. Thick nasal discharge is present in the right naris in conjunction with crusts on the nasal planum. At this time, these lesions were essentially unchanged since the initial examination. D—Photograph of the dog 20 weeks after the initial examination. The dog's stature is small and body condition is poor; at this time, the dog's appearance was essentially unchanged since the initial examination.

Citation: Journal of the American Veterinary Medical Association 232, 5; 10.2460/javma.232.5.715

Hematologic abnormalities included high WBC count (24.9 × 103 cells/μL; reference range, 5.2 to 13.9 × 103 cells/μL) characterized by a neutrophilia (18.92 × 103 neutrophils/μL; reference range, 3.9 to 8 × 103 neutrophils/μL) and monocytosis (2.49 × 103 monocytes/μL; reference range, 0.2 to 1.1 × 103 monocytes/μL). Results of serum biochemical analyses were within reference ranges. Thoracic radiography revealed diffuse nonstructured opacities throughout the lungs and mild bronchial thickening; the right caudal and cranial lobar pulmonary arteries were large. The result of a test for occult infection with Dirofilaria immitis was negative. Cytologic examination of a fine-needle aspirate of the left submandibular lymph node revealed neutrophilic inflammation.

The dog was anesthetized, and biopsy specimens of the conjunctival and gingival lesions were obtained. Substantial amounts of abnormal conjunctiva were excised from the right eye for therapeutic and diagnostic purposes. The right nictitating membrane, which was unrecognizable grossly because it blended with the thickened conjunctiva, was excised because it was impairing vision. Microscopically, the conjunctival biopsy specimens from both eyes were characterized by profuse amounts of eosinophilic, amorphous extracellular material with mild neutrophilic inflammation and glandular ectasia (Figure 2). Staining of the eosinophilic material with periodic acid-Schiff or phosphotungstic acid-hematoxylin stain yielded positive results, whereas use of Congo red or Alcian blue stain yielded negative results; these findings indicated that the material was fibrin. The palpebral conjunctiva and the conjunctiva of the right nictitating membrane contained foci of mineralization. The oral mucosal lesions similarly contained large amounts of extracellular, eosinophilic material. The lacrimal gland of the right nictitating membrane and its ducts were apparently normal. Pending the results of the histologic examination of biopsy specimens, the dog was treated with topical application of neomycin-polymyxin-bacitracin ophthalmic ointment, cyclosporine 2% solution, and hydroxypropyl methylcellulose lubricating gel in both eyes every 8 hours.

Figure 2—
Figure 2—

Photomicrograph of a section of the conjunctiva of the nictitating membrane. Notice the large amount of eosinophilic, amorphous extracellular material that is covered on 1 surface with conjunctival epithelium. On the basis of its staining characteristics, this material was identified as fibrin. H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 232, 5; 10.2460/javma.232.5.715

The microscopic findings, in conjunction with the ocular signs, were consistent with ligneous conjunctivitis, which is a chronic membranous conjunctivitis that rarely affects dogs.1,a Plasminogen deficiency was suspected in this dog because of the involvement of mucosal sites other than the conjunctiva and because ligneous conjunctivitis is linked to systemic plasminogen deficiencies in humans and mice.2–7 The result of a plasma plasminogen functional activity assayb,c was low (49%; reference range, 60% to 170%) and confirmed plasminogen deficiency.8 Analysis of a plasma sample submitted 3 weeks later revealed that plasminogen activity was 35%; in a clinically normal age-matched control dog, the value was 111%, and among pooled samples from other healthy dogs, the value was 118%. Minimally low plasma antithrombin III activity (98%; reference range, 100% to 156%) and lack of detectable plasma D-dimer indicated an absolute plasminogen deficiency rather than plasminogen consumption. The clinical diagnosis was a congenital plasminogen deficiency with secondary ligneous conjunctivitis, ligneous gingivitis, and membranous upper airway disease.

The dog was reexamined 16 days after the initial evaluation. The owners reported that the membranes had reformed and worsened within 5 days of excision. On examination, the conjunctival lesions had proliferated remarkably, resulting in blindness in the left eye and limited vision in the right eye. The cornea and intraocular structures were not visible in either eye. To provide plasminogen locally in both eyes, a single subconjunctival injection of FFP that had normal plasminogen activity (76%) followed by topical application of FFP (1 drop, q 2 h during waking hours) was initiated 1 month after the initial examination.9,10 Additionally, topical administration of 2% cyclosporine in both eyes (1 drop, q 6 to 8 h) was used to treat both the ligneous conjunctivitis and keratoconjunctivitis sicca.11–13 Because of the mucopurulent ocular discharge, baci-tracin-neomycin-polymyxin B ointment was used topically intermittently. None of these treatments had an appreciable effect on the membranes. Azathioprine (1 mg/kg [0.45 mg/lb], PO) was administered once daily for 14 days, then once every other day for 14 days, but was similarly ineffective. Administration of amoxicillin (11 mg/kg [5 mg/lb], PO, q 12 h) decreased the nasal discharge mildly and improved the dog’s cough. Clindamycin (5 mg/kg [2.7 mg/lb], PO, q 12 h) was administered for 14 days because of progression of the oral lesions, but was ineffective.

The dog was reevaluated 2 months and 3.5 months following the initial examination because of episodes of decreased appetite and lethargy; at both visits, the dog was febrile (39.8°C [103.7°F] and 39.5°C [103.1°F], respectively). The dog’s appetite and attitude improved and the fever resolved with the initiation of oral administration of antimicrobials. Thoracic radiography performed 3.5 months after the initial examination revealed mild nonspecific pulmonary interstitial infiltrates; a focal irregularity on the luminal surface of the trachea at the level of the thoracic inlet was detected. The owners were instructed to perform nebulization and coupage daily. Wet food and soft toys were recommended to decrease gingival irritation.

The dog was hospitalized for attempted surgical correction of ligneous conjunctivitis 20 weeks after the initial evaluation. Fresh frozen plasma (8 mL/kg [3.6 mL/ lb], IV) was transfused immediately prior to surgery in an attempt to increase circulating plasminogen activity. The dog was anesthetized and the conjunctival membranes were excised from both the superior and inferior palpebral conjunctiva in both eyes and from the bulbar surface of the nictitating membrane of the left eye while electrocautery was used to meticulously control bleeding. Heparin diluted with saline (0.9% NaCl) solution was used to flush the surgical site repeatedly, and FFP and tPA (250 μg/mL) were continually dripped on the surgical site to decrease the formation of fibrin. Once the conjunctival membranes were excised, the corneas were evaluated. The right cornea had small vessels extending from the dorsal limbus to the axial aspect, and a hazy, poorly defined subepithelial opacity was present in the axial region. In the left eye, a 2-mm, sharply defined, chalky, white opacity was detected in an immediately inferotemporal to axial location on the surface of the cornea. Following excision of the membranes and recovery from anesthesia, the dog was hospitalized for 14 days and treated in both eyes with topical administrations of heparin (1,000 U/mL, 1 drop, q 30 min to 2 h), tPA (250 μg/mL, 1 drop, q 1 to 2 h), FFP (1 drop, q 1 h), and 1% suspension of prednisolone acetate (1 drop, q 1 to 2 h) to limit the formation and deposition of fibrin. Tobramycin (0.03% solution; 1 drop, q 8 h) was applied to both eyes for bacterial prophylaxis until conjunctival re-epithelialization was achieved. In addition, topical ophthalmic administration of cyclosporine and oral administration of amoxicillin were continued. The dog also received 1 unit of FFP IV daily.

Within 48 hours of surgery and the initiation of plasma transfusions, the dog’s nasal discharge diminished substantially and subsequently resolved, and the oral lesions improved. The dog’s attitude brightened and appetite increased; it gained 0.9 kg (2 lb) during hospitalization. A mild hemorrhagic discharge from both eyes was present throughout the hospitalization period, but diminished after the frequency of topical administration of heparin was decreased to every 2 hours. By day 14 of hospitalization, the conjunctiva had minimal bleeding and appeared to be re-epithelialized, and the dog was able to see. Slit-lamp biomicroscopy revealed an incipient anterior cortical axial cataract in the right eye, which did not progress. The corneal lesions in both eyes also remained unchanged in the remainder of the follow-up examinations.

One day prior to the first plasma transfusion, the dog’s serum plasminogen activity was 48%. After 4 days of daily transfusions, plasminogen activity was 46% and 68% at 1 and 8 hours after the FFP transfusion. After 13 days of daily transfusions and the initiation of oral administration of danazol (5 mg/kg [2.3 mg/lb], PO, q 12 h), which is an anabolic steroid that can increase circulating plasminogen in humans, the dog’s plasminogen activity was within reference range (65% prior to transfusion and 71% and 74% at 1 and 8 hours after transfusion, respectively).14,15

At the time of discharge from the hospital (14 days after surgery), the owners were instructed to continue topical and oral administration of all medications with the exception of tPA. Twice-daily topical treatment with hydroxypropyl methylcellulose lubricating gel was included in the regimen.

Four weeks after surgery, the dog was reexamined and results of a Schirmer tear test were 15 mm/min in the right eye and 0 mm/min in the left eye. Because the ducts of both the lacrimal gland and gland of the nictitating membrane are intimately connected to the conjunctiva, the waxing and waning tear production in both eyes was attributed to the conjunctival lesions. The left inferior palpebral conjunctiva had a slightly thickened and red appearance, but the remainder of the conjunctiva was essentially normal, and the dog retained its sight. The frequencies of some topical treatments of both eyes were decreased (heparin [1,000 U/ mL, q 6 h], FFP [1 drop, q 4 h], 2% cyclosporine [1 drop, q 8 h], and 1% prednisolone acetate [1 drop, q 8 h]). Treatment with hydroxypropyl methylcellulose lubricating gel in the right eye was discontinued, and the frequency of administration in the left eye was increased (q 4 to 6 h).

Also at that reexamination, the owners reported that the dog had diminished appetite and lethargy. Slightly green nasal discharge had developed, and the dog had lost 0.68 kg (1.5 lb). Pronounced ptyalism with copious foamy, yellow-tinged saliva within the oral cavity was evident, and there was a pink, proliferative lesion affecting most of the soft palate. Because of the progression of the oral lesions and the worsening of the systemic signs, amoxicillin administration was discontinued and enrofloxacin (10 mg/kg [4.5 mg/lb], PO, q 24 h) and clindamycin (5 mg/kg, PO, q 12 h) were prescribed.

Results of a plasminogen assay indicated a dramatic decrease in serum plasminogen activity (10%; value for a control dog, 91%). A plasma sample from a control dog was mixed 1:1 with the patient’s plasma, and a plasminogen assay was performed; another plasma sample from the control dog was mixed 1:1 with saline (0.9% NaCl) solution and similarly assayed. Both assay procedures recovered equal plasminogen activities. This finding indicated that the patient’s low plasma plasminogen activity was a result of a true plasminogen deficiency rather than the presence of plasminogen inhibitors because the patient’s plasma did not decrease the plasminogen activity in the control plasma sample, compared with the effect of saline solution.d Treatment with danazol was discontinued, and the administration of the estrogenic compound diethylstilbestrol (0.3 mg, PO, q 24 h for 5 days then q 48 h) was initiated. In women, estrogen increases plasminogen activity, improves fibrinolysis, and may improve ligneous conjunctivitis.16–20 Five days later (28 weeks after initial evaluation), the owners requested euthanasia because of the dog’s inappetence and lethargy. On the final examination, the conjunctiva in the right eye was essentially normal in appearance. The conjunctiva of the left eye was coated in profuse, thick, mucopurulent discharge but was otherwise apparently normal. Cytologic evaluation of the discharge revealed a mixed population of bacteria. The dog had profuse ptyalism, and its body weight had decreased by 1.14 kg (2.5 lb) since the last visit. The proliferative lesion on the soft palate, nasal discharge, and cough were unchanged. The dog was euthanatized via IV administration of an overdose of pentobarbital and submitted for postmortem examination.

At necropsy, gross findings included ulceration and extensive multifocal to coalescing proliferative plaques throughout the oral cavity, nasopharynx, and trachea. Smaller numbers of similar plaques were present on the esophageal mucosa and both the thoracic and cardiac surfaces of the pericardium (Figures 3 and 4). Mild hydrocephalus, mild fibrinous perihepatitis, multifocal splenic capsular siderofibrotic plaques, and multifocal petechial intestinal mucosal hemorrhages were also identified.

On histologic examination, the plaques in the oral cavity, nasopharynx, trachea, esophagus, and pericardium were similar in appearance to those of the original conjunctival and oral biopsy specimens (Figures 3 and 4). The ulcerated mucosa had extensive fibrin deposition overlying atypical, poorly organized granulation tissue. In the sections of tissues obtained at necropsy, plasma cells and lymphocytes were the predominant inflammatory infiltrate. Fibrin thrombi were present within multiple small- to medium-sized pulmonary vessels and submucosal vessels in the oral cavity and trachea. There was a single locally extensive focus of pulmonary fibrosis with type II pneumocyte hyperplasia. In addition, there were multiple foci of alveolar septal mineralization and mineral casts within the renal medullary ducts.

Figure 3—
Figure 3—

Photograph of the gross appearance of the epicardial surface (A) and photomicrograph of the epicardium (B) of the dog in Figure 1. Multiple red to tan plaques and nodules representing fibrin are distributed across the epicardial surface of the ventricles and atria. Microscopically, the epicardial surface is irregularly thrown into papillary fronds supported by fibrovascular stroma and deposits of fibrin. In panel A, the marker represents 1 cm. In panel B, H&E stain; bar = 100 μm.

Citation: Journal of the American Veterinary Medical Association 232, 5; 10.2460/javma.232.5.715

Figure 4—
Figure 4—

Photograph of the gross appearance of the esophageal mucosa (A) and photomicrograph of the esophagus (B) of the dog in Figure 1. In panel A, one of the multiple nodular to papillary superficial lesions found throughout the esophagus is located in the center of the image. Microscopically, marked accumulations of fibrin extend over the focally exophytic lamina propria and the ulcerated to hyperplastic epithelium. There is minimal formation of granulation tissue. The luminal aspect of the hyperplastic esophageal epithelium is visible (arrowheads); the poorly organized dark blue fibrillar material overlying the epithelium is fibrin admixed with cellular debris. In panel A, the marker represents 1 cm. In panel B, phosphotungstic acid-hematoxylin stain; bar = 500 μm.

Citation: Journal of the American Veterinary Medical Association 232, 5; 10.2460/javma.232.5.715

Although the conjunctivae were grossly normal in appearance, histologic examination revealed multiple discrete foci of ulceration with fibrin deposition. The corneal lesions identified after surgery were characterized by corneal epithelial hyperplasia and squamous metaplasia with subjacent stromal deposition of fibrin and corneal vascularization.

In humans, ligneous conjunctivitis is a rare membranous conjunctivitis; it was so named because of the wood-like consistency of the membranes.22 The disease has been linked to a type I plasminogen deficiency, and several inherited mutations in the plasminogen gene have been identified as the molecular etiology.5,6,23 Diagnosis of the disease is typically made in infants, but the condition may develop at any age.24 The palpebral conjunctiva is affected most frequently, but the bulbar conjunctiva and cornea can also be affected.11,25,26 Other mucosal sites such as the gingiva, ears, respiratory tract, gastrointestinal tract, and female reproductive tract may be affected concomitantly or, occasionally, in the absence of conjunctival lesions.27–32 Congenital occlusive hydrocephalus, Dandy-Walker malformation, impaired wound healing, and kidney involvement may also develop.2,4,6,10,26,30,33,34 The ocular changes result in blindness, and the associated systemic signs are lifethreatening in severely affected individuals. In the dog of this report, the mucosal lesions in the conjunctiva, oral cavity, upper portions of the digestive and respiratory tracts, and hydrocephalus are consistent with findings in humans. Pericardial lesions have not been previously reported to our knowledge but were not surprising given the pathogenesis of this disorder.

The pathogenesis of the lesions in the conjunctivae and other mucosal sites involves dysregulation of the fibrinolytic pathway following minor mechanical injury to tissues. In clinically normal individuals, a fibrin-rich matrix provides hemostasis and is subsequently replaced by granulation tissue. Impaired proteolysis as a consequence of a deficiency in plasminogen results in the inability to remove the fibrin-rich matrix and remodel granulation tissue; thus, wound healing is arrested at the granulation tissue stage, and fibrin-rich membranous deposits accumulate. The high frequency with which the conjunctivae are affected, compared with other mucosal sites, is likely attributable to the frequent exposure of the conjunctivae to minor irritation with subsequent inflammation, which leads to exudation of fibrin and other plasma proteins and the formation of ligneous membranes.11 Minor surgical procedures may also result in the development of membranes and, as evident in the dog of this report, excision of membranes without prophylactic measures is typically associated with rapid reformation.10,13,29,35,36 Although there was evidence of limited multifocal intravascular thrombosis in the dog of this report, there is surprisingly no increase in the risk of intravascular thrombosis in humans with plasminogen deficiency, suggesting the existence of an alternative pathway for intravascular fibrinolysis.37

The diagnosis of ligneous conjunctivitis in humans is made on the basis of the clinical appearance of the conjunctival membranes, typical microscopic findings, family history of the disease, and serum plasminogen activity assessment. In the dog of this report, the diagnosis of ligneous conjunctivitis was made on the basis of the clinical appearance and characteristic histopathologic features. It is noteworthy that the initial clinical appearance in the left eye was not that of a typical membrane but was instead a nodule associated with the superior palpebral conjunctiva and a thickening of the posterior aspect of the nictitating membrane. Nodular masses in humans with ligneous conjunctivitis have been infrequently reported.4,13,35,38 The major histologic findings in affected mucosal sites in humans are extensive surface ulcerations with overlying or subepithelial deposits of amorphous hyaline-like eosinophilic material (primarily fibrin) and foci of granulation tissue and inflammatory cells.11,24 The histologic findings in the dog of this report were similar to those in affected humans.

For the dog of this report, results of several assays indicated low plasma plasminogen activity, and a plasminogen deficiency was confirmed. Because the clinical signs developed at such a young age, it is presumed that this deficiency was congenital. In humans, both plasminogen antigen and functional plasminogen activity may be measured; however, for use in dogs, only an assay for plasminogen activity is currently available.

Treatment of ligneous conjunctivitis and plasminogen deficiencies in humans and dogs is challenging. Several treatments via topical and oral administration have been attempted in humans, most with variable or no success.11 Intravenous administration of purified plasminogen was used successfully in a child that was severely affected with type I plasminogen deficiency; treatment resulted in a rapid regression of conjunctival membranes, normalization of viscosity of respiratory tract secretions, and improved wound healing.34 However, a purified plasminogen concentrate for IV administration in dogs is currently unavailable, and its usefulness would be limited by a short half-life (5 hours).34 Topical ophthalmic treatment with FFP preceded by subconjunctival injections was successful in preventing recurrence of ligneous conjunctivitis following excision of a membrane in an adult human.9 Topical ophthalmic treatment with FFP prior to excision of the conjunctival membranes was ineffective in the dog of this report, but IV and topical administrations of FFP in conjunction with topical applications of heparin, tPA, cyclosporine, and a corticosteroid following excision of the conjunctival membranes prevented recurrence of the abnormal tissue. Subconjunctival injections of FFP caused substantial hemorrhage from the conjunctival membranes and resulted in no improvement in the dog of this report. Topical administration of plasminogen concentrate seems to be more effective than FFP in people, but a commercial product is not available.10,29

A combination of medical and surgical treatments is currently recommended in humans with ligneous conjunctivitis and includes topical ophthalmic administration of a fibrinolytic agent (eg, plasminogen concentrate) and tPA followed by surgical removal of the membranes and intensive postoperative treatment with applications of topical heparin and corticosteroids, sometimes with the additional application of cyclo-sporine.11,36 This recommendation formed the basis of our treatment protocol for the dog of this report. Additionally, plasma transfusions were administered daily to the dog to determine whether donor plasma could improve the nonocular signs of plasminogen deficiency and measurably increase circulating plasminogen activity. The transfusions were given daily because of the known half-life of plasminogen in humans (24 to 26 hours). Excision of the membranes with effective hemostasis followed by intensive topical treatments with FFP, tPA, heparin, corticosteroid, and cyclosporine, in conjunction with daily IV plasma transfusions, was successful in preventing the regrowth of the dog’ conjunctival membranes. Although the postoperative follow-up period was short (55 days), this success is noteworthy in light of the rapid recurrence of the dog’s conjunctival lesions following the initial excision. The plasma transfusions were associated with weight gain, decreased nasal discharge, and improvement in the gingivitis and stomatitis, indicating that repeated plasma transfusions may be a viable treatment option for dogs with a plasminogen deficiency. Discontinuation of plasma transfusions was associated with weight loss, worsening of upper respiratory tract signs, and severe worsening of oral lesions. Although plasma transfusions were given daily in the dog of this report, it is possible that less frequent transfusions would be equally effective. The use of IV plasma transfusions for the treatment of plasminogen deficiency in humans has not been described to our knowledge.

Danazol was administered in an attempt to increase serum plasminogen activity in the dog of this report.14,15 However, plasminogen activity declined substantially and the clinical signs worsened after this treatment was initiated. The estrogen component of oral contraceptive medications increases plasminogen activity in women, and use of such medications has been linked with the regression of ligneous conjunctivitis.19,20 It is unknown whether estrogen increases plasminogen activity in dogs, and unfortunately, the duration of treatment with diethylstilbestrol of the dog of this report was too brief to permit an evaluation of efficacy.

In dogs with ligneous conjunctivitis, the administration of azathioprine has been recommended.1 In the dog of this report, there was no response to azathioprine. Azathioprine is unlikely to be effective in dogs with ligneous conjunctivitis secondary to plasminogen deficiencies, and drug-induced immunosuppression could increase the risk of pneumonia in dogs with concurrent respiratory tract involvement.

To our knowledge, this is the first case report of a dog with a congenital plasminogen deficiency and the first report of a link between a congenital plasminogen deficiency and ligneous conjunctivitis in a dog. In this dog, surgical treatment of ligneous conjunctivitis was successful; additionally, daily transfusions of donor plasma may be effective in treating the systemic signs associated with plasminogen deficiency in this species.

ABBREVIATIONS

FFP

Fresh frozen plasma

tPA

Tissue plasminogen activator

a.

Torres MD, Leiva M, Naranjo A, et al. Ligneous conjunctivitis in a dog: a case report (abstr), in Proceedings. 37th Annu Meet Am Coll Vet Ophthalmol 2006;25.

b.

Comparative Coagulation Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, NY.

c.

Stachrom Plasminogen, Diagnostica Stago, Parsippany, NJ.

d.

Marjory Brooks, Comparative Coagulation Laboratory, College of Veterinary Medicine, Cornell University, Ithaca, NY: Personal communication, 2006.

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