Webinar Session on Plasminogen Deficiency: Expand your knowledge

July 10, 2018

Expanding Your Knowledge of Plasminogen

This webinar will provide a comprehensive and timely overview on management of Plasminogen Deficiency, including strategies for coping with a chronic disease. In this webinar, you’ll learn - Causes of congenital Plasminogen Deficiency - Signs and symptoms - Testing and diagnosis - Treatment options - Consultation and care from specialists - The importance of being your own advocate - Connecting with others diagnosed with PLGD Want to learn more? Join the PLGD community here.

"Hello everyone, good morning or good afternoon- welcome to our educational session on Plasminogen Deficiency. Before i speak any further may i ask you to type 'yes' in the chatting box, i just want to make sure that you can all hear me properly. Perfect, so its coming in,  so I've got a few yes's so that means everything is working well - that's great.

So, again welcome and thank you for your participation. My name is Julie and i work here at Prometic under the rare disease division. We are extremely excited and happy to present an overview of Plasminogen Deficiency and we truly hope that you will expand your knowledge today. This session is going to be pretty simple. We will start with a 40 minute presentation with Dr. John Moran our Chief Medical Officer here at Prometic. Dr. Moran is well experienced and extremely knowledgeable about Plasminogen Deficiency, and then following his presentation we will have a Q&A session at the end where you will be able to ask a question to Dr. Moran. So without keeping you waiting any longer i will let Dr. Moran take over with this session and i hope you enjoy this session and again thank you very much for joining us today. So Dr. Moran i will leave it to you - thank you.

Thank you Julie. So, let me briefly introduce myself on the second slide, you probably guessed by now that i'm Australian.  I graduated from the University of Melbourne in 1969, a long time ago so i have a lot of experience. I'm board certified both in internal medicine and methology and I've been doing research for three decades or more as the slide says. I'm the Chief Medical Officer from Prometic Life Sciences and i have an Adjunct appointment from the Stanford University School of Medicine since I've lived in the Palo Alto area for the last ten years or so.

What is Plasminogen (PLG)?

So, lets talk about Plasminogen. It's a protein that's made by the liver and circulates normally in the blood, it activates a change- i'ts a substrate for an enzyme which leads to the generation of plasmin. Plasmin is a fraction of the the plasminogen molecule and has many important roles in the body but among the most important is dealing with blood clots. When your blood clots you have a network of fibrin or fibres which form the clot and stop the bleeding whether its a small cut or a large one. But, once you've stopped the bleeding you need to repair the wound so normal tissue comes in and removes that fibrin that stops the bleeding and replaces it with normal tissue or scar tissue. 

If you don't have plasminogen you have difficulty removing the clot and it becomes organised and forms what is called ligneous lesions. Ligneous is from the Latin, it means 'woody' and typically these lesions are firm and painless and only cause problems either if they're visual or they interfere with organ function. 

Congenital Plasminogen Deficiency (PLGD)

Sorry i got a bit ahead of myself, so i'm now looking at slide five. On the left you see what happens in a normal situation, a person with a normal level of plasminogen in the blood. Plasminogen is converted by normal body enzymes to plasmin and that breaks down fibrin and removes it so that the body can then repair the wound. If you lack plasminogen as is described on the right hand side of this slide, you are not able to generate plasmin and you are unable to remove that fibrin clot. It can cause either inflammation or organ damage if it's in the wrong places - if it's in an inconvenient place for the body.

It's a very rare genetic disease' we'll talk about the inheritance but its autosomal recessive so that means it's a very rare disease and the symptoms and signs, the manifestations of this occur when the level (of plasminogen) is low. So, here is a slide showing the inheritance - it's autosomal recessive - that means that each parents has one abnormal gene and one normal and so the possibilities of inheritance: you would get one gene from the father one gene from the mother- so you can see the possible combinations. If you are lucky and inherit both the normal genes from your parents you would be normal, you have a one in two chance of getting an abnormal gene from one parent and a normal gene from the other. So, you have a two in four chance of being a carrier. If you are unlucky and inherit the defective gene from each parent you'll have congenital plasminogen deficiency. So you can see how the numbers play out.

If each parent has one abnormal gene and one normal gene and in theory if they have four children they would have one normal child, two children which were carriers but would not have any manifestations of plasminogen deficiency and one in four of the children would have congenital plasminogen deficiency because they have been unlucky enough to inherit the defective gene carried by each parent.

Congenital Plasminogen Deficiency - Signs and Symptoms Recognition

So, we have bleeding in many places in the body, usually the skin but other sites as well and so the signs and symptoms of plasminogen deficiency depend on where the bleeding occurs, where the ligneous change occurs when the fibrin can't be removed and whether it interferes with vital function of whatever organ. I'm going to go through a list of the possible manifestations, you can see that there are many and so it's often difficult to diagnose.

Doctors have two problems in diagnosing this, first of all its a rare disease so they may not know about it, they may not think about it when they see a patient and secondly because it has so many different possible effects on so many possible organs it may be seen by many different specialist doctors. 

So, this slide shows a representation of essentially the body with possible sites where plasminogen deficiency may lead to problems and as you can see there are many and just about every organ in the body could be affected. Remember, its a very rare disease even if you have the congenital plasminogen deficiency you may have very few manifestations, very few problems - i don't want to get people alarmed that all of these organs could be affected. Generally we see one or two or three.

I'll run through the more common ones. So the eyes, these symptoms can cause Ligneous Conjunctivitis  and there is a representation of that here. It's by far the most common manifestation of this rare disease. We see it in about 80% of patients and there is probably two reasons for that; one is that obviously the lesions are very visible as you can see in this slide and secondly the eyes are exposed to the outside world probably more than any other body part, sorry any other organ except the skin.

Ligneous Conjunctivitis 

So, minor trauma to the eye such as getting a piece of dust in your eye and trying to remove it may cause a bit of bleeding, if that occurs then you may end up with a ligneous lesion. This cant be removed without causing problems, they often reoccur if there is no plasminogen available.

Ligneous Gingivitis 

So, another visible organ of course if the mouth and so called ligneous gingivitis that is inflammation of the gums can occur and that may lead to a number of problems including tooth loss, it may lead to disfigurement in the mouth and alveolar bone loss, the bone that is supporting the teeth may erode away. Ligneous gingivitis is fairly common in patients with congenital plasminogen deficiency so it may be diagnosed by a dentist for instance.

Skin

The skin, impaired wound healing. As i said the process of wound healing occurs in stages, the first the formation of the fibrin clot to stop the wound bleeding and then the normal tissue repair. If you don't have plasminogen you cant complete the wound healing and so wounds may close but have a lot of difficulty in healing. Remember wounds include surgical wounds, patients with congenital deficiency of plasminogen may have difficulty getting healing of even clean surgical wounds.

Respiratory Tract Obstruction

Respiratory tract obstruction, this is fairly uncommon but the issue here is that you can get ligneous lesions inside the respiratory tract in the trachea or bronchi and if they obstruct air flow then you get lung collapse behind the obstruction, you may or may not get infection on top of it. As i said its not a very common manifestation but it can be very severe. Obviously it depends which area of the lung and how much of the lung is damaged but its something that really has to be dealt with. Currently, treatment is to excise the tissue and remove the obstruction.

Occlusive Hydrocephalus

Congenital hydrocephalus, that's obstruction to the flow of cerebrospinal fluid, the fluid that supports the brain and stops it bouncing around the skull. If you get haemorrhage during birth as may occur inside the so called ventricles where the fluid is inside the brain, then you get obstruction to the normal flow of that brain fluid and pressure building up which can compress the brain and it has to be treated by relieving the pressure typically by inserting a shunt between the spinal fluid and the peritoneal cavity so there is an artificial route to drain the fluid and relieve the pressure. That shunt is usually required for life.

Genital Tract

in the genital tract especially the female genital tract you get such lesions in the uterus, the vagina, the ovarian tubes and it may be associated with infertility simply because of the obstruction in the genital tract and infertility is a relatively common manifestation in females with congenital plasminogen deficiency. Again, management is typically surgical excision of the lesions, its difficult to achieve success in the absence of plasminogen because as i mentioned a surgical wound is a wound and may have problems healing.

Plasminogen Deficiency- Diagnosing & Treatments

I think it should be diagnosed at first by an alert physician recognising the potential of plasminogen deficiency based on the problems the patient presents with and the first thing to do is to test the level of plasminogen in the blood. If the plasminogen level is below about half of what is normal the subject who has the typical lesions very likely has congenital plasminogen deficiency and genetic testing can be done to look at the plasminogen gene and find any mutations which are leading to decreased levels of plasminogen.

When a lesion is excised the pathologist can do a microscopic examination and it has a very typical appearance and that's another way the lesion may be found ans typically was the way the diagnosis was made before it was recognised a lack of plasminogen that caused the problem.

So, step one laboratory testing for plasminogen activity in the blood if the level is low the diagnosis should be confirmed with genetic testing and i should also suggest that if a child presents with congenital plasminogen deficiency then any siblings, brothers or sisters should also have their plasminogen levels tested as well because one sibling may have lesions before another even though they both have the same congenital deficiency.

So, current treatment options in the management of plasminogen deficiency. The saying in medicine that the more treatments there are for a condition the less likely each of them is to be successful; if there was a successful treatment  there would not be many treatments. Surgery at the moment is the primary approach when one really has to excise lesions that are dangerous to organ function or obstructing vital organs. Ligneous conjunctivitus is by far the most common manifestation and clearly those lesions need to be excised if they are likely to interfere with vision or if they are particularly distorting the eye or eyelids. 

Steroids, you can use either local steroids so called cortisols or equivalent. These reduce the inflammation but will not cause total resolution of the lesion. There are topical treatments that have been used with varying degrees of success, quite a lot of them immunosuppressive agents such as you would give an organ transplant recipient so significant drugs which may cause issues should not be used lightly.

Fresh frozen plasma has been has been the standby, you take plasma from a normal person who has a normal level of plasminogen and infuse it into the patient. But if you do the fairly simple math, one litre of fresh frozen plasma infused into a patient who has a zero plasminogen level will only raise the  level by one in five. You're infusing one litre of plasma into a circulating blood volume of five litres so you would only get the level up to one fifth or twenty percent and of course there is a limitation of how much fresh frozen plasma you can give. Especially in infants or young children there is a very limited volume you can give. Experience with fresh frozen plasma is very variable, patients with significant levels even though they have the lesions you may be able to resolve the lesion with fresh frozen plasma either intravenously as i mentioned or local eye drops but very very often you simply cannot get enough plasminogen into a patient with congenital plasminogen deficiency because you're infusing just plasma with a normal level which is diluted by the patients own plasma.

Plasminogen Deficiency - Circle of Care

I've mentioned that very many specialists may see the patient and therefore very many specialists involved in both the diagnosis and management. The Opthamologist will most likely be the first person to diagnosis the condition simply because as i mentioned ligneous conjunctivitis is by far the most common manifestation. It is unfortunately such a rare disease and opthamologist's have to think about diagnosis, consider the diagnosis. The lesions have a very typical appearance and should be diagnosed quite easily once the doctor thinks about the condition but as i mentioned its very rare and therefore very few opthamologist's have ever seen a case. 

The dentist may diagnose it if there is gingivitis and again it's less common than ligneous conjuctivitis and very few dentists will ever see a case but they may be the person who diagnoses it. Pediatrician- manifestations may occur at birth for instance with congenital hydrocephalus or ligneous conjunctivitis may occur within a few months when the baby is exposed to the external environment. Neurologists, if a child presents with hydrocephalus then the neurologist has to work out why and one of the reasons for congenital hydrocephalus has to be ruled out is congenital plasminogen deficiency. Nephrologist's, again renal tract involvement is uncommon but does occur and usually manifests itself as bleeding in the urine or obstruction of the tubes passing urine to the bladder, the uterus. The lung specialist (Pulmonologist) may see it, patients with obstructive lesions in the lungs typically that would be followed up by having a look down at the lungs at the lesions and excising the lesions if they're obstructing the free flow of air. But again the pulmonologist has to think about the condition, this very rare condition.

So, in the center of this, the circle of care we've put the hematologist, as really its a disease that's related to a lack of plasminogen in the blood and its the hematologist who will be monitoring the person from that point of view and should be following the patient for life and referring the patient to other specialties as required to deal with lesions in specific organs as we've listed on the outer circle. 

For all the reasons I've just mentioned it's important for the patient to understand their disease, i think its a great saying in medicine 'the patient should know more about their disease than the doctor.' Especially in a condition like this which is so rare and has so many different possible presentations, symptoms, signs it's very important for the patient to be educated about the condition so that they can in turn ensure that the physician understands the disease. You may end up educating your doctor as is usually the other way around. I think you need to be aware of potential issues and if they occur draw them to the attention of your doctor and if you're educated you may well be able to suggest what is required.

So, the plasmingeon deficiency community (PLGD community) - patient organisations, especially with rare disease are very very important. There is mutual support, mutual education and understanding of the disease which is so important in such a rare disease. We have put a link here to the website which is for one of these patient organisations which has a lot of information there and i invite you to go to that site, educate yourself and also just as important let other patients and their families know about this site.

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