Treatment of Ligneous Conjunctivitis Using Topical Plasminogen Therapy in an 8-Week-Old Female Infant.

An 8-week-old female infant presented with bilateral eyelid swelling and conjunctival membranes. She was diagnosed as having ligneous conjunctivitis. The membranes were excised but recurred despite topical cyclosporine, heparin, fresh frozen plasma, and systemic fresh frozen plasma transfusions. Topical plasminogen prevented membrane recurrence and intravenous plasminogen therapy treated systemic manifestations of the disease. [J Pediatr Ophthalmol Strabismus. 2018;55:e30-e32.].

Topical Plasminogen as Adjunctive Treatment in Recurrent Ligneous Conjunctivitis.

Ligneous conjunctivitis is a rare, autosomal recessive, membranous conjunctivitis characterized by a deficiency in type 1 plasminogen. The absence of normal plasmin activity results in the formation of fibrin-rich, membranous material that typically manifests on the palpebral conjunctiva. Surgical treatment often causes irritation of the conjunctiva and accelerated recurrence of pseudomembranes. In this interventional case report, the authors document the results of treatment with topical plasminogen following conjunctival pseudomembrane excision in a 32-year-old woman. The patient underwent pseudomembrane excision in the OS followed immediately by hourly topical application of plasminogen eye drops. The plasminogen was prepared from pooled human plasma purchased under Food and Drug Administration approval from DiaPharma. Follow-up evaluation at 1 week, 1 month, and 5 months showed no evidence of recurrent pseudomembranous change. Adjunctive topical plasminogen application appears to be an effective and safe method of controlling pseudomembrane recurrence in patients with ligneous conjunctivitis.

Beyond hemostasis: the challenge of treating plasminogen deficiency. A report of three cases.

Congenital plasminogen deficiency is a rare autosomal recessive disorder, characterized by chronic mucosal membranous lesions. Although the most common clinical manifestation is eye involvement as ligneous conjunctivitis, extra-ocular lesions affecting other mucosal surfaces indicates a systemic disease. In this report we describe two cases with atypical extra-ocular involvement that includes pericarditis and recurrent hematocolpos, and one with paradoxical correlation between ocular lesions and plasminogen levels. In ligneous conjunctivitis, although different treatment strategies have been tried with mild success, the only effective therapy is topical or systemic plasminogen concentrates that are not commercially available. Unfortunately there is not either effective management for cases with multisystemic disease. Hence, treatment for plasminogen deficiency is still a challenge and the variability of the clinical spectrum in this pathology makes necessary a multidisciplinary approach.

Treatment of ligneous conjunctivitis with topical plasmin and topical plasminogen.

PURPOSE: To describe treatment of a child with recalcitrant ligneous conjunctivitis secondary to a systemic plasminogen deficiency. DESIGN: Interventional case report. METHODS: A seven-year-old boy developed severe unilateral membranous conjunctivitis recalcitrant to surgical debridement and treatment with topical prednisone, topical cyclosporine, and oral prednisone. Systemic evaluation revealed a severe plasminogen deficiency. RESULTS: Treatment with surgical debridement and topical plasmin was ineffective and resulted in prompt recurrence of dense conjunctival membranes. Treatment with topical plasminogen resulted in dramatic improvement and complete resolution of the membranes. CONCLUSIONS: Ligneous conjunctivitis is secondary to a systemic plasminogen deficiency. Treatment with topical plasminogen resulted in prompt resolution of the membranes. Treatment with topical plasmin was ineffective.

Angiogenesis inhibitors in lung cancer.

Lung cancer is a major public health problem and the leading cause of cancer-related death worldwide. Its survival rates have changed little over the past 20 years. The best clinical benefit (ie, survival rates) with combination cytotoxic therapies in non-small-cell lung cancer (NSCLC) may have been reached. The need for improved survival rates in NSCLC has driven the development of novel, rationally designed, targeted therapies. Inhibitors of angiogenesis have been developed and are increasingly studied. Potential targets for therapy include inhibitors of vascular endothelial growth factor receptor, endogenous angiogenesis inhibitors, and cyclooxygenase inhibitors. Combining targeted molecules with traditional cytotoxic therapies usually results in lower required chemotherapy doses and fewer, less severe side effects. A number of ongoing randomized studies are underway to evaluate this idea. It is anticipated that these new targeted therapies will play an important role, along with cytotoxic and radiation therapies, in the management of metastatic disease.

Acute tissue damage after injections of thrombin and plasmin into rat striatum.

BACKGROUND AND PURPOSE: Extravasation of blood is associated with intracerebral hemorrhage and head trauma. The mechanism of brain cell injury associated with hemorrhage differs from that due to pure ischemia. The purpose of this study was to investigate the acute changes after intracerebral injections of proteins that are involved in blood clotting and clot lysis. METHODS: Sixty-eight adult rats were subjected to stereotaxic intrastriatal injections of normal saline (5 microL), low- (2.5 U/5 microL) and high-dose (25 U/5 microL) thrombin, low- (0.1 microgram/5 microL) and high-dose (1 microgram/5 microL) tissue plasminogen activator, low- (0.05 U/5 microL) and high-dose (0.5 U/5 microL) plasminogen, and low- (0.335 U/5 microL) and high-dose (3.35 U/5 microL) plasmin. Forty-eight hours later rats were perfusion fixed. Brain damage area, eosinophilic neurons, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive cells, infiltrating neutrophils, CD8a immunoreactive leukocytes, and reactive microglia were quantified. RESULTS: Damage area in striatum, dying cells, inflammatory cells, and microglial reaction were significantly greater after the high-dose plasminogen, plasmin, and thrombin injections. Tissue plasminogen activator injections were associated with mild inflammation. CONCLUSIONS: These results suggested that thrombin and plasmin are harmful to brain cells in vivo. Although the doses required to cause damage are relatively great in consideration of the plasma content of these proteins, their pathological effect might be enhanced through synergism with other mechanisms.

Thrombolytic treatment with tissue-type plasminogen activator (t-PA) containing liposomes in rabbits: a comparison with free t-PA.

In this study, we aimed at improving the therapeutic index of tissue-type Plasminogen Activator (t-PA) as thrombolytic agent in the treatment of myocardial infarction. Liposome-encapsulated t-PA was tested in a rabbit jugular vein thrombosis model: administration of free t-PA (t-PA) as a bolus injection in the ear vein was compared to a similar administration of liposomal t-PA (t-PA-lip), liposomal t-PA in plasminogen-coated liposomes (Plg-t-PA-lip), a mixture of free t-PA and empty liposomes (t-PA+ empty lip) and a saline-blank (blank) in terms of thrombolytic activity and side effects. Liposomal t-PA (t-PA-lip/Plg-t-PA-lip) showed a significantly better thrombolysis efficiency than equimolar doses of free t-PA (t-PA/ t-PA+ empty lip): about 0.24 mg/kg of liposomal t-PA practically equalled the lysis-activity of a dose of free t-PA of 1.0 mg/kg (t-PA1mg/kg). On the other hand, liposome encapsulation did not affect the systemic activation of alpha 2-antiplasmin and plasminogen by t-PA. We conclude that for this model an improvement in thrombolytic efficacy of t-PA is achieved by liposome encapsulation of t-PA. As t-PA-lip and Plg-t-PA-lip -treatment induced similar results, targeting of liposomal t-PA by coupled glu-Plg remains a topic to be optimized in future studies.

Preclinical pharmacological evaluation of anisoylated plasminogen streptokinase activator complex.

An ideal thrombolytic (or fibrinolytic) agent is one which would generate the formation of plasmin only where it is required, i.e. bound to fibrin within the thrombus. However, the capacity of even the newer thrombolytic agents to achieve localised plasmin generation within the thrombus is relative and depends on the concentration of the agent administered. For all available activators, the concentration required for effective clinical thrombolysis is also capable of converting plasminogen to plasmin within the circulation (plasminaemia). Since the action of plasmin is not specific to fibrin, plasminaemia results in dissolution not only of fibrin but also of several other clotting factors. For example, plasmin can degrade fibrinogen and cause impaired haemostasis. The plasminogen activators which are available, or have been developed to date, include streptokinase, urokinase, pro-urokinase, anisoylated plasminogen-streptokinase activator complex (APSAC) and tissue plasminogen activator (t-PA). All of these agents have the same biochemical mechanism of action, cleaving an arginine-valine bond in the plasminogen molecule to form plasmin, but they differ with regard to other important properties. The first property to be considered is clot specificity; the ability to dissolve fibrin as opposed to fibrinogen, and also to dissolve the clot as opposed to a haemostatic plug. Unfortunately, fibrin specificity does not equate entirely with thrombus specificity, and all currently developed plasminogen activators, by dissolving fibrin, will induce the destruction of haemostatic extravascular plugs as well as intravascular thrombi. Thus, no agent is thrombus-specific in this respect. The degree of fibrinogenolysis does vary between plasminogen activators. Those which have the least effect on haemostasis or clotting capability would seem, at first, to be preferable. However, a short term reduction in fibrinogen could also be beneficial, since it may reduce the incidence of early reocclusion and, by reducing blood viscosity, improve microcirculation to the infarct zone. The intrinsic efficiency of the plasminogen activators is a second important property. In vitro, under conditions pertaining to the circulation, urokinase is about 10 times more efficient than t-PA at converting glu-plasminogen to plasmin (on the basis of the Vmax to Km ratio), while streptokinase-plasmin is 20 times more efficient. The efficiency of these activators is increased in the presence of fibrin and lys-plasminogen, 1800-fold for t-PA, 8-fold for urokinase and 180-fold for streptokinase-plasmin.(ABSTRACT TRUNCATED AT 400 WORDS)