What is primary myelofibrosis?

- Primary Myelofibrosis is a disorder where you have connective tissue and fibroblasts, that's what fibrosis is, so connective tissue or fibroblasts being produced in the bone marrow, that's what myelo means. Now primary myelofibrosis means that this happens on its own, because there are other types of myelofibrosis associated with the other myeloproliferative disorders. So that means that primary myelofibrosis is a disorder wherein the the shaft of long bones like the femur or other places in your body you make bone marrow, remember these sites are important to make cells like this pluripotent, meaning having the ability or the potency to make many or plural things, hematopoietic, meaning related to the blood, stem cell. So this is a pluripotent hematopoietic stem cell. It has the ability to make a variety of cells we find in the bloodstream. So here I'm just drawing out the lymphoid stem cell lineage up here is the myeloid stem cell lineage we're going to talk about in more detail, while the issue in primary myelofibrosis is that the marrow in the femur is just replaced with connective tissue, making it difficult to produce these pluripotent hematopoietic stem cells or the myeloid stem cells and eventually red blood cells white blood cells or even platelets. You've just got a dry bone marrow. You don't have the blood cell-producing apparatus you need. So one thing that might come to mind is that if we're not making these stem cells in the bone marrow, well where do we make it instead? And the explanation is that primary myelofibrosis often occurs with what's called myeloid metaplasia, which you might recall myeloid means related to the bone marrow and then metaplasia in this instance indicating that the bone marrow is made elsewhere, and that elsewhere in fact will be in your liver, will become bigger, that's why I drew it like this, so it can accommodate the extra function of producing hematopoietic stem cells. Your spleen develops the same sort of role, it'll also grow bigger like this to accommodate the extra function of producing stem cells for the blood cells we have in our vasculature. And this can all be traced back, this fibrosis in the bone right here, to a JAK2 kinase mutation. Now this should be a familiar buzzword to you, because this is the exact same mutation you have in polycythemia vera and in essential thrombocythemia. But the main difference is that the defect will happen very early on, here in the bone marrow, which then compromises the production of other cells that should come off of these stem cells later on. And I'll draw them out right here for completeness, so we can reference them in our conversation. So the important thing to realize is that the cells that we are supposed to be producing here from our bone marrow because they're not being made, cause us to have signs and symptoms associated with their deficiency, or their absence, and this will produce certain characteristic signs and symptoms such as abdominal fullness, which I think we already alluded to, which is associated with the growth in your spleen, which is turning it into a mega-spleen, or we call this situation splenomegaly, and when this happens in the liver as well, giving you hepatomegaly, you have in total what's referred to as hepatosplenomegaly. So hepatosplenomegaly. You can also get bone pain, because rapid fibrosis in the bone marrow will impinge on the nerves there. And then beyond that we can start to think about what happens when we're lacking the cells we should be making in the bone marrow. For instance when we don't have platelets which should be clotting when we have cuts to our blood vessel, we end up having unregulated bleeding, which could manifest as either having nosebleeds, or what are called ecchymosis, ecchymosis which is just a fancy term for bruises. And these will happen when you bump, let's say you're walking in crowded room and you bump your thigh into a table or a chair, even a slight knock can produce a very serious bruise when you're deficient in platelets. Now when you're deficient in in red blood cells you can start to look paler, so you'd have some pallor, or, because you don't have enough red blood cells to get oxygen throughout your body, perhaps you'll have some dizziness as well. And again, this is due to having decreased number of red blood cells, and then the bleeding is due to a decreased number of platelets. And then finally with a decreased number of white blood cells, you can develop what are called opportunistic infection, because the low white blood cell count you have makes you relatively immunosuppressed, giving infectious organisms like bacteria and viruses the opportunity to attack. Now, how do we diagnose this? Well one of the first things you can do is get a complete blood cell count and you'll notice that you have a decreased number of red blood cells and platelets. You may also have an increased number or immature white blood cells. Another thing you can do is look at your blood in a microscope, that's called a peripheral blood smear, and that'll show red blood cells with an unusual shape. They'll look like teardrops, as you can see in this image here. Now while we might have some relatively normal-looking red blood cells like this, you've got these teardrop-shaped red blood cells that indicate that these cells are passing through a fibrotic bone marrow, which causes them to shear and have this unusual shape. So let's minimize this. And then moving on, sort of the last two things you can do, is look directly at the bone marrow. You can do a bone marrow aspirate, meaning try and draw up some of the bone marrow with a big needle, and notice that you don't get much, we say this is a dry tap, or the bone marrow is dry. And that indicates that we're not really producing things in the femur, because we have fibrosis there. And then at that point some people might elect to do what's called a bone marrow biopsy, which means instead of taking a large needle to suck up some of the bone marrow, you go in and take out a chunk using a big needle as well. And by doing this biopsy you can see some fibrosis. Okay. Now what can we do to treat primary myelofibrosis with this myeloid metaplasia? Well, fortunately there's one cure, and that is to replace the fibrosis that's there with other stem cells. And so you'd have to do what's called a stem cell transplantation. Sometimes while we wait for the opportunity to do a stem cell transplantation, patients may be given a transfusion of blood cells that they're missing to increase their red blood cell count, or even their platelet count. And finally one of the other things we can do that I guess I should mention here, because primary myelofibrosis with myeloid metaplasia is actually the most common cause of splenomegaly in anyone above age 50 years old. The last thing we can do is what's called a splenectomy, because if the spleen gets so big that it's impinging on vessels, and causing too much abdominal fullness where the patient is so uncomfortable and in pain, we'll have to get rid of it. Now primary myelofibrosis is a pretty uncommon disease, with some very interesting pathophysiology, and it all goes back to thinking about what are the functions of these cells, and when we don't have them, what ends up happening to give us certain signs and symptoms, and then what do we need to look for, to really indicate that this is the issue we have here in our bone marrow? And then what do we do to treat it?