DIP Episode 4 - Hematology A

Hello, welcome. My name is Devine. This is a fourth divine intervention episode. Today I'll be talking about hematology. I have about 10 or 11 keywords slides I want to go over. And just as sort of like a full warning, this is probably one of those podcasts that you don't want to listen to at elevated speeds, which I know we all do as medical students, or I guess as healthcare professionals. Because this one contains a fair number of head scratchers, but if you sort of try to follow along, things will make perfect sense. One, two, you would have very little, you actually do need to memorize and three. You will actually be able to make some inroads into other, I guess, fields of learning like biochem or cell biology. Okay, because those are the ways they try to integrate this material on board exams. And yeah, so let's go ahead and start. So the first question says slide 1 A. Genetics of often beta thalacemias, right? So the thalacemias are essentially problems involving global gene production. Okay. And remember that numohymoglobin, that's hemoglobin A is alpha to beta 2. Okay. So if you have problems with alpha gene production, that's alpha thalacemia. Okay. And in general, alpha thalacemia is found primarily in like West Africans and in Asians. Okay. But beta thalacemia is found more in the Mediterranean population. So the quip genetics that I want to talk about here is that we have alpha chains.

Basically, we have like four genes that actually I guess two genes that control the production of alpha chains. We get two genes from mom to genes from that. So we have four genes total. But for the beta globin chain in hemoglobin, we do in fact have only one gene. Okay. And again, if you get one from mom and one from dad, okay, you form, you have two genes total. And the problem with alpha thalacemias is in general, you have like a gene deletion that prevents you from making alpha, the alpha chain in hemoglobin. But in beta thalacemia, it's almost always like you're making less beta globin. And it usually arises at least I will say in terms of the classically tested concept on exams in the context of a splicing defect. So splicing defects may, you're not necessarily having any problem on the gene transcription level. But you're having problems more with pre-translational regulation of the gene product. So just sort of something to keep in mind there. Now, the protective antisidants with thalacemias, people think that thalacemias are common in like African countries because it protects against the bug that one of the bugs that causes malaria, okay, plus modium falsyperum. Remember that plus modium species are the staying positive with the game's estate, okay? So if you see like an exam question, the test they can thin smears blah, blah, blah. Think about like, think about plus modium species and also Babesia species.

Remember Babesia is carried by the x-edistic that also carries line disease that's a burriable durfrey and a plasmosis. Okay, so let's talk about the number of the different permutations for alpha thalacemia. So the thing is we say there are four genes, right? And basically you have problems based on the number of genes that are gone, number of gene deletions you have. In general, if you have only one or two gene deletion, you have like a very subclinical course. In fact, those patients are usually symptomatic. But if you then get into losing three or four genes, then you have some very serious problems. But let's first discuss what happens with losing two genes. So if you think about it, you can lose two genes in one of two ways. You can lose both genes, I guess in one of three ways. So you can lose both genes on that chromosome, like the chromosome you get from that. That's a cis mutation. Or you could lose both genes from mom's chromosome, the chromosome you get from mom. That's also a cis mutation, or you could lose one gene from dad and one gene from mom's chromosomes. That's a transmutation. Those cis mutations are commonly found in Asians, but the transmutations are commonly found in West Africans. Now why is that important? The reason in there is that the cis mutations are usually more severe than the transmutations. Because the way I sort of think of it is, if you're losing one gene from mom or from dad, you have one other gene to help you out somewhere.

But if you're losing both from mom, let's assume that has not so perfect genes. And you don't have some good genes from mom to counterbalance that. You could sort of envision how you could run into troubles with that. And if you lose three genes, three alpha-changes, you have something known as hemoglobin-H disease. And in hemoglobin-H disease, the thing that happens is that, because there is very few alpha-gins around, beta-globin says, I got to marry someone. So beta-globins begin to pair up with themselves. So you form like beta-fotetromers, and that's the classic finding on a hemoglobin-electrophoresis in a person that has three genes gone. And just real quick, if you have two alpha-gins gone, that is what is known as alpha-thalacemia trait, so just something to keep in mind. Now, if you lose all four genes, unfortunately the child is not born. And the reasoning behind that is, if you really think about the hemoglobin that's present in utero, hemoglobin F, it contains alpha-2 and gamma-2. If you have no alpha-gins whatsoever, then you begin to have the gamma-globin-chains pairing up with each other to form gamma-4. And basically, those kids have very severe anemia in utero, they get like hydroxythalac and all that badness, and they're just basically never born, okay? It's lethal in utero. Now, another question I pose after this is, how can a child of two alpha-thalate trait parents have hemoglobin-barts?

So hemoglobin-barts, sorry I didn't mention this earlier, is the problem you get when you lose all four alpha-chains. Hemoglobin-H disease is the problem you get when you lose three alpha-chains. So ask yourself, so this is one very nice way to contest genetics and cell biology on your exam. For a kid to have hemoglobin-barts and have two parents that have alpha-thalacymyatrate, which is what you get when you have 12-gins gone, you could potentially imagine that the kid has two parents that both have the cis alpha-thalate trait, right? So what do I mean by cis again? By cis I mean that, oh, each parent like the mom had only two copies of the alpha gene, and she potentially lost like the other two copies from like one chromosome, either from mom only or from dad only, right? And then for dad, he also had two copies lost of the alpha-changing, and he probably lost it all from either his dad's chromosomes or from his mom's chromosomes. So if the genetic material that is passed on from the parents to the fetus is the defective gene that has lost both chromosomes, sorry that has lost both alpha-sorry, so if the chromosome that was passed on from mom to the fetus or from dad to the fetus was the chromosome that lacked those two alpha-changing genes, then the kid will essentially have no alpha-changing genes, and they'll have hemoglobin-barts, which again like I said is lethal in utero. Now, beta-thal minor, so we said there are two total beta-thalacymyatrate genes.

If you lose one, you have something called beta-thal minor, okay? And if you have less beta-globin available, right? Anything that contains beta-globing gene-chains will go down, and anything that does not contain beta-globing chains will go up, right? So hemoglobin A, we said it's alpha-2 beta-2, so your hemoglobin A levels go down a little in beta-thal minor, your hemoglobin A2 level. So remember, hemoglobin A2 is alpha-2 delta-2, that goes up in beta-thal minor, and remember, hemoglobin F is alpha-2 gamma-2, that also goes up in beta-thal minor, okay? And if you're trying to compare ion deficiency anemia and beta-thal minor, right? Because both of them will present as a micro-sidic hypochromic anemia. So some things that can help is that the ion studies in ion deficiency anemia abnormal, but the ion studies in beta-thal minor are totally normal. So what do I mean by that? What I mean is that if you check like the ferritin and the serum iron and the serum transferring saturation and all that fun stuff, it's all normal in beta-thalacymyatrate. And another thing that may also help with differentiating ion deficiency anemia from beta-thalacymya minor is the fact that in beta-thal minor, what was I thinking of with this? Well, let's see. Yes, so in beta-thal minor, you may occasionally find target cells on a blood on a microscopic or blood smear. So that's another way to tell beta-thal minor apart from ion deficiency anemia.

Okay, sorry if you with all these arms and ass, most of these lectures I'm giving them from memory. Okay, so beta-thal major, beta-thal major is when you've lost both beta chains, so both of the genes are gone. And most of those problems with beta-thal major actually show up six months after birth. The reason behind that is for the first six months of life, you still depend primarily on hemoglobin F, which has alpha-2 gamma-2. So you don't necessarily have this big need for beta-globin chains until about six months after you're born. Okay, but for hemoglobin H disease where you've lost three of your four alpha-globin chains, you begin to run into trouble from birth because again at birth, you need alpha chains for that fancy hemoglobin F. If you have fewer alpha chains, then you'll begin to have very severe anemia. A very severe anemia from the time you're born. Okay, and again, with regards to the smear findings, you'll classically find target cells in the thalacinias, although remember the target cells also found like in liver disease, for example. And these thalacinias classically present in a kid that has like some kind of hemolytic anemia, they have increased reticulosides because they're destroying their red cells left right and center. And in addition, these kids usually have like this crew caught appearance on imaging, right?

Because they have a lot of extramedulary hematopoestus because it's like, oh, you need so much hemoglobin, you need so many red cells because your life span is sort of shorter because they are destroyed quickly. So you begin to make red cells in areas where you ordinarily don't do that in major quantity, like the bones that lie in your skull and things like that. So next slide. Hemoglobin in electroforesis findings in beta thalmy, major. Right, so we said in beta thalminar, your hemoglobin A goes down, but your hemoglobin A to an F go up. In beta thalmy, major, you actually have an increase in hemoglobin A to an hemoglobin F more severe increases, but you actually have absolutely no hemoglobin A on hemoglobin electroforesis. And again, because hemoglobin A has alpha to beta to, if you have no beta globin chains at all, then you will not form any kind of hemoglobin A. Now, next question says, A-plastic crisis in a patient with a history of beta thalmy, major. The thing I'm thinking about here is parvo B19. Okay, remember, in patients that have these hemoglobin apathies, parvo B19, remember it, preferentially infects erythroid precursors. So these kids add increased risk of A-plastic crisis with this single stranded DNA bottle. Okay. Remember the association with a slapped cheek rash. Okay. Now, elevated ferritin and decreased TIBC in a patient with a chronic histro beta thalmy, major. Right, so if you have beta thalmy, major, you're constantly hemolizing your red blood cells.

At some point, you become transvision dependent. And the thing is, when you're transfusing blood, you're helping the patient, but in addition, you're giving them a ton of iron. Okay. And that the body has very few means of getting rid of iron. In fact, the way the body regulates how much iron is in the blood at any given point in time or the total body iron stores, if you make, is by regulating the absorption of iron in the GI tract. So if you're just giving a person iron like IV, for example, and you're bypassing that system, you can begin to see how the person can have a lot of iron build up and get secondary hemochromatosis. That is why the ferritin will be elevated. And if your ferritin is high, remember there is an inverse relationship between ferritin and TIBC. The ferritin is high, the TIBC goes down. And remembering hemochromatosis, we maintain to get symptoms much later in life because menstruation is essentially a very effective means of getting rid of extra iron in the body. Okay. Now, the classically tested vitamin replacement with the hemoglobin apathesis is a replacement of folate. Because those people have very huge amounts of red cell turnover and they always make in red cells all the time, they need something that will help with DNA synthesis. So remember that folate is important in the conversion of deoxyroidin monofosophyt to deoxythymedin monofosophyt under the action of thymidilates synthetics.

Thymidilates synthetics uses the reduced form of folate, tetrahedral folate as a cofactor, so something to keep in mind. And if a person has beta thal major, they will basically have hemolosis of their red cells. So they will have the kinds of labs you see in a person that has a hemolytic anemia if you may. So they will have decreased haptoglobin because remember haptoglobin binds up heen. They will also have an indirect hyperbilarobinemia because by breaking down those red cells that heen is ultimately converted by the action of hemoxygenase and bilivereinary ductase to indirect bilirobin. Okay. So just something to keep in mind. And the combined hemoglobin apathesis, I'll just say this in the context of sickle cell disease. If you have hemoglobin SS where you have like sickle cell disease, you have very severe disease. But if you have hemoglobin S and some other kind of hemoglobin apathesis, like hemoglobin C disease for example, or hemoglobin, like one of these are thalacymias for example, on your other beta globin gene chain, you tend to have, it's usually still severe, but it's not as severe as having like hemoglobin SS. So just something to keep in mind with that as well. Now, slide number two, a patient with a histra of amalgamancy involving a 15-17 translocation begins to bleed severely after surgery. PT, PT and D-dimer are all markedly elevated. What's your diagnosis? The first thing we need to consider here is this person has a 15-17 translocation.

So this is most likely a hematologic malignancy in this case, AML. Acute myloid leukemia. And you can even be more specific and say that this is the M3 subtype according to the old classification system. This is an acute pro mylocytic leukemia. When you have an acute pro mylocytic leukemia, the classic histologic finding is that thing known as an hour rod. So if the person is getting surgery for this leukemia or they are getting chemotherapy, if those hour rods are released into circulation, those hour rods can actually activate and trigger the coagulation cascade. So these people can basically have a DIC picture. And in DIC, the way I think of the labs is you're just globally screwed. So what do I mean by being globally screwed? Your PT, anything that can go out of whack, goes out of whack. So your PT goes up, your PT goes up, your D-dimer goes up, your bleeding time goes up, your platelet count goes down. And the reason behind that is, if you are constantly activating the coagulation cascade, the first thing you do is you're depleting your clotting factors so you have an increased risk of bleeding. But the thing is, the coagulation cascade is known as secondary hemostasis. What do you need for secondary hemostasis to occur? Primary hemostasis. So if you're constantly depleting your clotting factors, I thought I imagined that, oh, you're also constantly activating primary hemostasis and you're depleting your platelets. So you get a thrombocytopenia.

And in addition to that, your bleeding time goes up because your platelet count is going down. And again, by losing all your clotting factors, you have an increased risk of bleeding. But all those clotting factors that you've depleted have formed clots all over the body. And those clots, those are thrombi. One thing they can do is they can share red cells that are passing through the vasculature. So you could potentially observe schistocytes on a blood smear. So that would be an example of an ultra-vascula hemolosis. So just something to keep in mind with that. So that's the path of physiology. And again, your platelet count will be low. You'll find schistocytes on a blood smear. Other classic causes include like a help syndrome. Help syndrome can present in a DIC-like picture. Let's see what else. A mniotic fluid embolism can present in a DIC picture. If a person is septic from a severe infection, he can present in a DIC picture as well. And if you want to differentiate between vomulibrancy disease and hemoglobin, I mean, hemophilia A, B and C. The thing is, hemophilia A is a deficiency of factor 8. So the mnemonic you'll learn as you're studying for step 1 is that hemophilia A sounds like 8. So hemophilia A sounds like 8. And then hemophilia B, like B, B9. So hemophilia B is a deficiency of a factor 9. And then hemophilia C is a deficiency of factor 11. And the first two hemophilias, right? So hemophilia A and B, in herithet in an exling, excessive fashion.

So it should only be boys that should have that on your test. Hemophilia C is passed on in an autosomal recessive fashion. So boys and girls can have hemophilia C on your exam. Now, how do you distinguish between this and vomulibrancy disease? Which is a deficiency of a vomulibrancy factor. The thing is, those hemophilias, right? So factors 8, 9, and 11 are all involved in the intrinsic coagulation cascade. Okay? They have no part in the extrinsic coagulation cascade. So the only thing that will go up is your PTT. There will be no change in your PTT. Okay? But if a person has vomulibrancy disease, if you have a deficiency of vomulibrancy factor, your platelet count should be normal, because it's not a quantitative platelet problem. But your bleeding time will be elevated, because your platelets are not working so well. In addition to that, vomulibrancy factor, in addition to its role in primary hemostasis, which is where it basically serves as the officiating minister between subendothelial collagen and GP1 B. It also acts as a protecting group for factor 8, so it increases the half-life of factor 8. So if you have a deficiency of vomulibrancy factor, factor 8 has a reduced half-life. And if it has a reduced half-life, your PTT will go up, because you sort of have some problems with your intrinsic coagulation cascade. Okay? So your PTT and your bleeding time are up in vomulibrancy disease, but in all the hemophilias, the only thing that will go up is your PTT.

Now, in the hemophilias, so hemophilias are clotting factor deficits. When you have clotting factor problems, you tend to get more delayed, but very severe bleeds. The classic bleeding pattern on the exam is a hemathrosis. So you're bleeding into your joints, or bleeding into muscle beds, for example. But if you have bleeds from platelet problems, you tend to get more superficial bleeds, right? So like the TKI, or bleeding after a dental procedure, or heavy menoragia and stuff like that. Okay? So those are things to think about. And the bleeds for platelet bleeds are more acute, they are more immediate as against the clotting factor bleeds that are usually more delayed. And another thing to keep in mind, so you may wonder, why do you have superficial bleeds with platelet problems? So the reasoning is, at least if I remember in this correctly, it appears that platelet secret certain cytokines that maintain adherence junctions between epithelial cells. So if your platelet counts are down, and you're not making those fancy cytokines that maintain adherence junctions between epithelial cells, then your epithelial cells will not be able to stick together very well, and you can begin to have like migration of blood across those cells, if you may. So you may have like PTKI. Okay? So that's one potential pathopathy physiology, but I'll probably wouldn't worry super, super much about that for the board exams. Okay. Now, the Ristocitin co-factor acid, right?

So basically, this is a test of platelet adhesion. Okay? Remember, platelet adhesion involves the binding of GP1 B to subendophilial collagen by using vomulibrands factor as a go-between. Okay? So if you have any problems in any of that, you would have an abnormal Ristocitin co-factor acid, because Ristocitin's job is to encourage that striper-tight relationship between subendophilial collagen, vomulibrands factor, and GP1 B. So, vomulibrands disease, because you have a deficiency of vomulibrands factor, will be associated with an abnormal Ristocitin co-factor acid. Bernat-Soulier's syndrome disease, where you have a deficiency of GP1 B, will also be associated with an abnormal Ristocitin co-factor acid. And how do you treat vomulibrands disease? You actually treat this disease by giving at least a mild form, I think it's like the type A form of vomulibrands disease. You give that by giving decimal pressing, okay? That's more pressing increases the release of vomulibrands factor from wibopaladi buddies. Okay? Now you find in endothelial cells. Okay? So by increasing the release of that stored vomulibrands factor, if you may, you can sort of relieve the symptoms of vomulibrands disease. And just as an aside, remember that in platelets, platelets actually also contain vomulibrands factor, when you find that vomulibrands factor in alpha-granules, not dense granules. dense granules are the things that contain ADP. The alpha-granules are the things that contain vomulibrands factor.

Okay? So next slide, slide three. So Ristocitin co-factor acid, on light microscopic observation of material, obtained from a lymph node biopsy. So what am I talking about here? I hope you're thinking of Hodgkin's lymphoma. Okay? So remember those cells that, those, the Ristocitin co-factor cells are like cells that look like glasses. And they look like, basically it's like a bilateral, outside inclusion in a B cell. And what are the types of Hodgkin's lymphoma? So there are four types, I guess, that you need to worry about, for example. There is, and the easy way to remember is just remember that there's like, oh, the lymphocyte issues, and then there's the mixture issues, and then there's the nodulesclerosin type. So why do I break them down that way? The thing is, the best prognosis, Hodgkin's lymphoma is the lymphocyte predominant, Hodgkin's lymphoma. The worst prognosis, Hodgkin's lymphoma, is the lymphocyte depleted, Hodgkin's lymphoma. Okay? And then in the middle, you have one known as the mix cellularity one. Okay? That's the one that comes right before, the lymphocyte depleted, Hodgkin's lymphoma in a bad prognosis, like if you're ranking by bad prognosis. And then the nodulesclerosin one is the one that comes right after the lymphocyte predominant, Hodgkin's lymphoma in terms of prognosis.

So from best to worst prognosis, we have lymphocyte predominant, nodulesclerosin, which is actually the most common kind of Hodgkin's lymphoma, mix cellularity, and lymphocyte depleted. And the classic CD markers in Hodgkin's lymphoma, a CD15 and CD30. Okay? Although there's a kind of lymphocyte predominant Hodgkin's lymphoma where you don't have that CD30 positivity, but that's like super loyal for the board. Now, what is the one general rule that relates to prognosis? I will say the one general rule is, the more it's termbaric cells you have, and the less lymphocytes you have, and the more extra weird cells that you have in Hodgkin's lymphoma, the worse your prognosis, right? So, and again, that should sort of make sense. If you're thinking of all these immune therapies that have come on board recently, by encouraging your immune system to do its job, you have a better prognosis in many cancers. So, less lymphocytes, so fewer, I guess, fewer lymphocytes, more rich termbaric cells, and more other cells, besides lymphocytes, pretend a bad prognosis in Hodgkin's lymphoma. And one way that your friends at the NBME could test Hodgkin's lymphoma in the context of bio statistics is to remind you that there's a bi-modal distributed of Hodgkin's lymphoma, right? So, it shows up in younger adults, and then shows up in the older population. So, that's something to keep in mind.

Another classic way to test that relationship is if you're comparing fast and slow acid leaders, say, for example, with isoniasid exposure. Remember, that's part of the reason why you get drug-induced lupus with your anti-histonantibudys and with isoniasid use, okay? So, there's a bi-modal distribution, there's slow acid leaders, and there's fast acid leaders. So, something to keep in mind. Now, the book that's classically associated with Hodgkin's lymphoma and many other hematologic malignancies is the Epstein-Bar virus, okay? Remember, the Epstein-Bar virus is her piece four. Okay, so, next slide, a discussion of primary hemostasis, plus some quick pulmonary-form association. Okay, so, basically, primary hemostasis has four parts, okay? The first part is, let's assume you get hacked by some annoying medical school classmate, okay? And you begin to bleed. The first thing your body says is, so you don't bleed, what's the quickest way can sort of tampon out of that bleed if you may. The quickest way for you body to fix that problem is to visual-constrict the vessels that are feeling that bleed, okay? And your body actually uses endothelene to make that happen. Now, this is where the pulmonary-form association comes in. That endothelene, if we know that endothelene is a powerful visual constructor, it should make sense that blocking endothelene receptors should promote visual dilation.

In fact, endothelene receptor antagonists like Ambrecentan, which blocks endothelene A receptors only, and Bocentan, which blocks endothelene A and B receptors, they are used to treat pulmonary hypertension. So remember, if you have like a lady that's in her 30s, that presents with dyspnea and chronic hypoxia, and tell you that Oshin has like right heart failure symptoms, think about pulmonary-atrial hypertension, secondary to like a BMP or tumultation, okay? So, visual constriction is the first step. The next step is, by hacking those blood vessels, right, you expose subendothelial collagen. That subendothelial collagen can bind to something known as vomulibrands factor, okay? vomulibrands factor has two sources. It can come from the alpha granules of platelets, or it can come from the wibopaladi buddies of endothelial cells. And while we're on the subject of buddies, I'll just take a small quick detour, right? So we said wibopaladi buddies, they contain vomulibrands factor, you find them in endothelial cells. Two classically tested structural things that you find in different cell types on step one or one. I remember your lamella buddies in your titaniumocytes. Those lamella buddies are basically the storage forms of surfactant, so something to keep in mind. Next one is your burbank granules that you find with pulmonary lunger hand cell histiosytosis, okay? I remember that's like S-100 and CD-1 A positive, so those are just things to keep in mind.

Okay, so back to this, right? So subendothelial collagen binds to vomulibrands factor, and vomulibrands factor then binds to GP-1 B. So vomulibrands factor is a go-between between subendothelial collagen, which you find below endothelial cells, and GP-1 B, which you find on the surface of platelets. So that's the adhesion step of primary hemostasis. When that process happens, your platelets begin to release some stuff, okay? One thing they release is, and oh, sorry, sorry, sorry, real quick. Just some quick times, if you have a deficiency of GP-1 B, that's Bernatelier disease, okay? If you have a deficiency of vomulibrands factor, that's vomulibrands disease, right? So continue, right? So we've talked about the adhesion step. Now, we said after that adhesion step happens, your platelets begin to release a bunch of random stuff, right? So like thromboxin E2. Thromboxin E2 is a promoter of the next two steps of primary hemostasis, which are activation and aggregation, okay? So if you have an anti-plitelet drug, you potentially want to decrease the synthesis of thromboxin E2. And it so happens that thromboxin E2 is made by cycloxygenase, cox-1 and 2. So if you inhibit that cycloxygenase irreversibly with a drug like aspirin, okay? You could decrease the synthesis of thromboxin E2. And when you decrease TXA2 synthesis, you prevent platelet aggregation and platelet activation. Now, another thing that's released by platelets is ADP, okay?

That ADP can come and bind to the ADP receptor. The ADP receptor is a G, so that's a kind of, I guess, an auto-crain regulation, right? Because the platelet is releasing something that acts on a receptor found on the surface of platelets. So that ADP binds to the ADP receptor. And when you have that binding, that ADP receptor is actually GI coupled, okay? So by being GI coupled, it's a G protein coupled receptor. It inhibits the activity of a denilite cyclase. So you convert less ATP to cyclic AMP, okay? And those low levels of cyclic AMP are coupled to the expression of GP2 B3 A on the surface of a platelet, okay? That expression of GP2 B3 A is the sort of triggers the aggregation step of primary hemostasis. But this whole business I've described with ADP binding to the ADP receptor and reducing the levels of cyclic AMP within the platelet, that's the activation step of primary hemostasis, okay? And then that GP2 B3 A basically binds to fibrenogen, which is also known as factor I, okay? And that fibrenogen, so it's like, think of fibrenogen as having like two ends, okay? If one end binds GP2 B3 A from one platelet, the other end binds another GP2 B3 from another platelet, then you have the aggregation step of primary hemostasis. You sort of form the platelet, the temporary platelet plug, okay? Now some pathology and some pharmacology with that is one. We have anti-plitlet drugs that can inhibit the platelet activation step, okay?

And if you notice I'm being very specific with these like steps. The reason one being specific is these board exams have been known to talk about a drug and also ask what's the step of primary hemostasis that is inhibited, okay? So it's the activation step that can be inhibited by a drug that blocks the ADP receptor. This ADP receptor is also known as the P2 Y12 receptor, okay? And if you block that receptor, you will sort of shut down that signaling cascade that leads to platelet activation. And drugs like clopidogrel, right? So it's an irreversible ADP receptor blocker or drugs like prostagrel or clopidin or ticagrelular. Those are all ADP receptor antagonists. So, okay, remember, ticlopidin actually has an association with thrombotic thrombocytopenic paper. We'll talk about those platelet drugs in another podcast. Now, another pharmacology time, right? We said high cyclic AMP equals, sorry, we said low cyclic AMP makes a platelet activated. So, high cyclic AMP should make a platelet inactivated, okay? And it so happens that the enzyme that breaks down cyclic AMP is phosphodisturize, okay? For purposes of our discussion, let's zoom in on phosphodisturize 3, okay? So, if you inhibit phosphodisturize 3, your cyclic AMP levels will build up and your platelets will not be activated, okay? So that's how drugs like selloster zone and diperidamol work. They prevent the breakdown of cyclic AMP with acts to inhibit the activation of platelets.

And just as an aside, cyclic AMP does two different things, right? So, in cardiac muscle, cyclic AMP encourages cardiac muscle contraction, but in smooth muscle, elevated levels of cyclic AMP actually promote relaxation, okay? So, that is why a drug like selloster zone is actually used to prepare for a lateral disease. Because by inhibiting phosphodisturize and boosting your cyclic AMP levels, you have a relaxation of smooth muscle, so you have better profusion of the stenosed vessels that line your legs, okay? Now, another time here is that we have drugs that can also block the GP2 B3 receptor, right? So, these drugs, they are inhibiting the aggregation step of primary, hemostasis, right? So, drugs like apsexema, which is a monoclonal antibody, and small molecules like eptypapatide and tyrophiban, work by blocking the GP2 B3 receptor. You could alternatively make autoantibodies against the GP2 B3 receptor in a disease known as ITP, okay? Ibn Thromosidopenica Piopera. And remember that that disease has a very strong association with systemic lupus, okay? So, something to keep in mind. Now, I've talked about the restoseating co-factor as a, right? So, obviously, we have normal invoindolibranes disease and brinatulis syndrome, okay? I've talked about the two high-oats versus a invoindolibranes factor, okay? The alpha granules of platelets and the wibol, paladibodies of endothelial cells.

And to increase the release of a wibranes factor, we've talked about how you give this more present for that, okay? Because, again, it increases the release of a wibranes factor from a wibopaladibodies. And you may say, oh, man, how does this make any sense? Well, let me give you a teleologic explanation, okay? The thing is, ADHD, its job is to maintain your blood volume. If you're bleeding, your blood volume will not be maintained, right? So, if you're clot of bleeding, you stop losing blood volume. So, you should make sense that hormone ADHD in this case, that tries to maintain blood volume, should promote the activity of something that causes clotting, okay? So, just something to keep in mind with that. Now, two high-oativators of platelets thromboxin A2 is a powerful platelet activator. Another high-oativator is thrombin factor 2, factor 2 actually activates platelets as well. Okay, let's see. And then, a high-oativator of platelet activation aggregation, there'll be PGI2, okay? PGI2. So, PGI2, just remember it as a platelet gathering inhibitor, if you may. PGI2 analogs actually used to also treat pulmonary arterial hypertension, because they are also very nice viso-diiliters. So, remember your drugs like cartroprostonial or ipoprostonial or iloprost. Those are all PGI2 analogs that I used to treat pulmonary arterial hypertension, because they raise the levels of cyclic AMP in smooth muscle. Okay. And I will have to look this up, so don't quote me on this.

But I think PGI2 actually works through either G, actually I think it's a GS coupled, a G protein coupled receptor, right? So, if you again, if you act through GS, you know, cyclic AMP levels will go up, okay? And that sort of explains how these drugs could act as good viso-diiliters, remember I said that high levels of cyclic AMP cause smooth muscle relaxation. In fact, just give me like a quick 30 second break, then I'll just check on this PGI2 business. So, PGI2, receptor, okay. Yep, it actually works through GS coupled receptors. Perfect. Good. So, let's go ahead and move on to slide five. Okay. So, categorizing anemias. Right. So, anemia is basically, there's three kinds of anemias, right? So, as a friend Uncle Pathoma would say, there's micrositic anemias where your MCV is less than 80. There's normal siliconemias where your MCV is between 80 to 100. And then there's micrositic anemias where your MCV is greater than 100. Okay. The classic causes of micrositic anemias include things like phallacineas or anemia of chronic disease or lead poisoning or cyderoblastic anemia. And I guess there's a few other causes we can talk about that later. For your normal cyric anemias, mainly think about your hemolytic anemias.

So, problems where you have like either old antibiotics being formed against your red cells, or you have like a structure red cell deficit like hair detraceous, cytosis or elliptosythosis, or you have an enzyme deficit like a G6 PD deficiency or pyrograde kinase deficiency. And then your macrositic anemias think of those in the context of either liver disease or B12 or full-eats deficiency. Okay. And the next part says 50-year-old male presenting with iron deficiency anemia. The thing I really want you to think about here is colon cancer. Okay. The next step in management for that patient will be a colonoscopy because colonic malignancies can bleed chronically and present as an iron deficiency anemia, classically people that are more than 50 years old. Now, the pathophysiology of microsytosis, right? So, I sort of think of it this way. Red cells, they try to maintain a very specific hemoglobin concentration. Okay. They try to keep their hemoglobin concentration within like a good range, if you may. Okay. And remember from general chemistry in college, concentration is mass over volume. Okay. So, if you have very low levels of hemoglobin, okay, because you have, remember, hemoglobin contains iron. So, if you have like low levels of hemoglobin, the mass, right? So, the numerator in that concentration measure goes down.

So, the way you can keep that concentration constant, if the mass is going down or the numerator is going down, is by also decreasing the denominator, decreasing the MCV of your red cell. Okay. So, that potentially explains the microsytosis you're getting the microsytic anemones. But the thing is, there's a certain volume that your red cells can get to where gas exchange becomes like super inefficient. And it's not worthwhile to shrink the red cell any further. Okay. So, if you have like just this hemoglobin deficiency over, over, over, over long periods of time, you hit a certain small size of red cell where your blood is like, you know, and I can't shrink this red cell anymore. So, let me then not look pretty as a red cell, okay? And then you begin to present with the hypochromasia that you get with hypochromica, microsytic anemones. Now, for microsytosis, the problem is you have a deficiency in stuff that helps with DNA synthesis, right? So, if you have like a folate, which is vitamin B, minor, B2, deficiency, you can make DNA very well. And remember, when you're making DNA, right, you're usually making it for a cell to divide. So, if a cell has increased in size first, but you're like, man, there is no DNA for me to add to this new big cell, new daughter cells. And beginning to form, you can sort of imagine that you stay as that one big cell that was ready to divide. So, you get a microsytosis, okay?

Now, next slide, different sheeting for high-ill but wear diseases, okay? And for probably like 12 of these diseases, our discuss pathophysiology, because that's also classically tested on these board exams. But let's go by vignette, right? So, how for patients? So, patient A is a 7-month old with very low red cell numbers. White blood cell and platelet counts are completely normal. The MCV is 107. Physical exam is notable for a cleft palate. So, this patient has something called diamond black fan anemia, okay? Diamon black fan anemia. And in diamond black fan anemia, classically, shows up in a kid that's less than a year old on exams, okay? And the only thing that is usually abnormal are their red cell numbers. Their white cell numbers and their platelet numbers are usually just fine, okay? And usually these kids have a macrosytic anemia, okay? And they usually have like cranioffical defects, like cleft lip or cleft palate, okay? And the pathophysiology here is people think that this involves problems with ribosomal proteins, okay? So, something to keep in mind there. Now, patient B is a 2-year-old with a history of malabsorption and fat-solable vitamin deficiencies. He's in the first percentile for height. His white cell count is low, with an especially non-utrophil count, but platelet and red cell counts are normal. He visits an orthopedic surgeon frequently for recurring skeletal problems. So, this kid actually has something known as schwaqman diamond syndrome, right?

So, here's why they love to test this disorder, right? Because it's very easy to mix this up with diamond black fan, right? They both have diamond in the name, okay? What patient A, we said had diamond black fan anemia. Patient B has schwaqman diamond syndrome. Schwaqman, I believe, is spelled as SH, WACH, M-A-N, okay? So, schwaqman diamond syndrome. We said in diamond black fan, the problem was you have very low levels of red cells. In schwaqman diamond, you have very low levels of neutrophils. But, classically, on exams, your platelet counts and your red cell numbers are usually just fine, okay? So, what are the other findings in schwaqman diamond syndrome? Other findings include a short stature, right? So, like, first percentile for height. The attempt to have skeletal problems, right? That's why I talked about having to visit orthopedic surgeons all the time, okay? And a very, like, a super, super high-yout finding is pancreatic exocranian sufficiency, okay? So, remember, if your pancreas is not, if you're not squirting all those light business, for example, you will not reabsorb your vitamins A, D, E, and K, your fat soluble vitamins, okay? So, that's why the kid has, like, fat soluble vitamin deficiencies, right? So, like, if you don't have an old vitamin A, you have, like, visual problems. If you don't have a vitamin D, you can get, like, rickets, right? Remember, rickets, you have a vitamin D deficiency. So, you have a secondary hyperprime thyroidism with that.

And let's see, for vitamin E, you can have, like, bleeding problems, also the same thing on vitamin K, okay? So, things to keep in mind. So, that is shwakman diamond syndrome. Now, patient C, pathophysiology doesn't really matter for that one. Now, patient C has a history of severe bleeding after dental procedures, recurrent infection with encapsulated organisms, and severe anemia, right? So, this cluster tells you that they probably have problems with the entire blood cell line, right? So, the bleeding after dental procedures, they may have, like, pleatlet problems, they have recurrent infections, so they may have, like, white cell problems, and they have severe anemia, so they may have red cell problems, okay? And here's the kicker. This kid has no thumbs on his left hand. I guess you can't have two thumbs on one hand. So, let's change that to one thumb. So, he has no thumb on his left hand. A radio bone is not possible on physical exam. And this kid has coffee or late spots, okay? Which are visualized on the face and trunk. This is fancone anemia, okay? So, please, please, please, do not mistake fancone anemia for fancone syndrome. Fancone syndrome is coming up soon. This kid has fancone anemia. And on, like, damn on black fan anemia, where you just had predominantly a red cell problem, or shwakman diamond syndrome, where you had primarily a white cell problem, most, like, most, most specifically, neutrophilts. In fancone anemia, you have problems with every cell.

So, you have, like, white cell, red cell, and pleatlet problems, okay? Now, the pathophysiology here, classically, is a person that has problems fixing double-stranded DNA breaks, okay? One of the ways you fix a double-stranded DNA break is with something called non-homonal gas and joint. So, if you have problems in that process, okay? You have, like, hipoptosis and death of many of your blood cells, okay? So, that's what you observe in fancone anemia. And the classic findings, coffee or late spots, okay? So, please, do not think coffee or late spots are just in neurofibromatosis. You can also get coffee or late spots in an all-bright hair distrust your dystrophy, and you can see right now, get it in fancone anemia as well, okay? So, if you see a kid with low levels of everything, okay? And they have problems with their thumbs, okay? Problems with their radial bones, like the radius, think about fancone anemia. As a bonus for your peach shelf in the future, there is a disease known as thrombocytopenia absent-radiocendrom. A tar syndrome, basically, in that syndrome, those people have low levels of platelets, okay? And they have no radius. But, on like fancone anemia, they have no problems with their thumbs, okay? But that's loyal for now. That's more for pediatric shelf. Now, patient D has a history of a non-anion gap metabolic acidosis. He also has a history of recurrent nephrolithiasis with urine, microscopy revealing stoneship like benzene rings.

There are high levels of multiple electrolytes in his urine. He has brittle bones, brittle bones, okay? So, this patient does not have fancone anemia. This patient has fancone syndrome, okay? Fancone syndrome, for your exam, think of it as presenting more with kidney problems, okay? More specifically, think of it as presenting with proximal renal tubular problems. And we know that the proximal renal tubular is the workhorse of the nephron, right? So, if you have like a global transported deficit in the proximal convoluted tubular, you can begin to envision that a patient would have problems with reabsorbing many electrolytes. That's why you see multiple electrolytes in the urine, okay? And remember, if your proximal tubular is non-functional, okay? You have a tytonal tubularcydosis, okay? Remember, your RT As are an example of the non-anion gap metabolic acidosis, okay? So, this patient will have a tytonal RTA, okay? And remember, this is one of the type, the RT As that has an association with hypochylemia, but the urine pH is just fine, okay? The urine pH is just fine. Remember, the only hyperchylemic RTA is a tytonal RTA, where you have low levels of our nostril. Okay, now, why does this patient have recurring lepharolithiasis? And you see urine stones that are shipped like benzene rings. Remember, that cysteine is reabsorbed in the proximal tubular. Okay? So, if that cysteine transporter is not working, which is one of the findings in Fankone's syndrome, okay?

Those cysteine stones will persist in the urine and cause lepharolithiasis. Okay, remember, those cysteine stones, they have six sides, okay? And good and the money days are cysteine sounds like 16, okay? So, they have six sides. Remember, benzene rings have six sides. And they also have brittle bonds because they're not reabsorbing phosphate, okay? Almost all of the phosphate that's reabsorbed in the nephronis reabsorbed are the proximal convoluted tubular. Okay, remember the transporter that does that process is inhibited by the phosphate trashing hormone PTH. Okay? So, again, if you have a global transporter deficit, you can a lot reabsorbing phosphate, you can potentially have rickets as a kid, okay? Or osteomyelasia if you're an adult. And just as a corollary here before I go to the next slide, with, I don't know if you remember, if you guys remember the cola transporter deficit, if you have a deficit, in fact, let's see, cola transporter. I believe that's heart-nub disease. So, cola transporter, okay? So, cola transporter deficit, sorry, I'm a fourth year. So, one of these things, we're beginning to forget them, unfortunately. Cola, one second. Okay. I think it's heart-nub disease, let's say heart-nub disease. Okay. Oh, now that's neutral amino acids. You know what? Let's call it cola transporter deficit. I'll have to find out more about that to see if the disease has an actual name. Okay?

Well, that cola transporter deficit, remember the C in that cola in cola stands for Sistine. Okay? So, you can have Sistine stones in the urine, okay? So, you can get a Sistineosis with that as well. Okay. So, now we're done with that. So, again, patient A had diamond black van anemia, patient B had shrockman diamond syndrome, patient C had vanconia anemia, patient D had vanconia syndrome. Okay? These diseases present very similarly or have very similar names. So, I said sort of catalog everything for you on one slide. Okay. So, question seven. Question of secondary hemostesis. Woo. Okay. So, a lot of factor names are going to be thrown around in short order. Okay? And we'll talk about some pathologies associated with secondary hemostesis as well and some pharmacology and the clot busters. Okay. So, basically we have two pathways of secondary hemostesis. So, the thing is, primary hemostesis helps you form a temporary pleated plug. But that little plug is not super ideal. Okay? It's not super ideal. But it helps you as a temporary measure. You need something that's a little more permanent. And that more permanent thing is secondary hemostesis. And there are two pathways of secondary hemostesis. There is the intrinsic pathway that starts with factor 12 and that's struct with a PT. And then there's the extrinsic pathway that starts with factor seven and that is struct with a PT or the INR. Okay? So, let's discuss the intrinsic pathway first.

So, basically in the intrinsic pathway, you'll start with factor 12. Okay? Factor 12, you convert it to factor 12a. Okay? Factor 12a then converts factor 11 to factor 11a. Okay? Then factor 11a converts factor 9 to 9a. Okay? Now factor 9a with the help of factor 8a helps you convert factor 10 to factor 10a. Okay? Now, factor 10a helps you convert factor 2 to factor 2a. Factor 2 is also known as thrombin. Okay? And it uses factor five as a help meat in that process. Okay? And then factor two, when it's converted to 2a, right? That 2a converts factor one, which is fibrenogen. Right? Remember, if that was the thing we said bound to GP2 B3a to factor 1a, which is fibren. Okay? And you form a stronger, pleclet mesh. And factor 13 actually helps. Factor 13 is sort of like on its own. It's not involved in the entire cascade. The only thing is sort of does is at the end, it comes and sort of stabilizes those fibren. Mesh is really well. Okay? So, that's the intrinsic cascade. The extrinsic cascade is much simpler. That's with factor seven. Okay? And usually tissue factor is the activity of that process. Tissue factor is actually known as factor three. So, factor seven is converted to sevena. And then, sevena also helps you convert in factor 10 to 10a. Okay? And then 10a, like we said, uses factor five to convert to 2a and 2a converts factor one to onea. And then factor 13 stabilizes that fibren mesh. Okay? So, that is the basic part of a secondary hemostesis.

But let's talk about some associated physiological concepts. First thing is factor two. Okay? Factor two has many tasks that it plays. Okay? One really plays is it activates the accelerating factors of secondary hemostesis. Right? So, the accelerating factors are the things that I said that, the service help makes for other clotting factors to make stuff happen. Right? So, we said, for example, if you were going from factors 10 to 10a, factor ninea could do that with the help of factor eighta. Factor eighta is an accelerating factor. Okay? And we said in the conversion of factor two to twoa by factor 10a, factor 10a, co-opted a help made factor fivea to help with that process. So, to actually make factor eighta from factor eight and factor fivea from factor five, you do need factor two to make that process happen. Okay? Another high-youthing that's done by factor two, thrombin, right? Is that again, it converts factor one to onea. And then another high-yout function is that factor two also binds to something known as thrombomodulin. Okay? To help you convert protein C to something known as activated protein C. Okay? Activated protein C is useful in the sense that it combines with its co-factor factor S to inhibit factors five and eight. Okay? Sorry. Yeah, to inhibit factors five and eight. Okay? So, easy way to remember that is factor two helps you activate factors eight and factor five. Okay?

What factor two can also bind pair up with a body thrombomodulin to make something activated protein C that joins up with a co-factor protein S to help you make, to help you activate the active forms of factors eight and five. Okay? Now, antithrombin three is something that helps you in activate factors ten and factor two. Okay? Remember, antithrombin three is super activated by heparin, right? To inhibit that factor ten and two. Okay? Contrast that with lumulecular with heparin that activates antithrombin three to help you in activate just factor ten. Okay? Now, if a person takes a heparin, you follow them with a PTT, but if a person takes lumulecular with heparin where you're just inhibiting factor ten, you do a factor ten as they to follow those levels. Okay. Now, Warfarin is an inhibitor of something known as vitamin K boxer reductives. Well, who cares about that? Well, let me show you why you should care. The thing is, factors two, seven, nine, and ten and protein CNS, as produced by the liver are not active. Okay? To become active, you need to gamma carboxylate these clotting factors. Okay? And these proteins. So, the thing that helps you gamma carboxyl leave those factors is the reduced form of vitamin K. Okay? So, vitamin K does the reaction, you gamma carboxyl leave those fancy things and you're good to go. Okay? But in that reaction, vitamin K is converted from the reduced form back to its oxidized form. Okay?

So, if you want that reaction that you love to keep going, you need to keep vitamin K in the reduced state. Okay? Keeping vitamin K in the reduced state is done by an enzyme known as vitamin K boxer reductives. Okay? That enzyme is inhibited by Warfarin. Okay? And that is why, if a person is taking a Warfarin, you give the anti-quagulant effect because you're not making reactive forms of factors two, seven, nine, and ten. Okay? And then your clot busters because if you've made the Fibrein mesh, you also don't want to keep a Fibrein mesh forever. Okay? That's not ideal because you could potentially have like a scheme of an organ, which is again not good. But it actually has a system in place to break down Fibrein to Fibrein degradation products. That role is undertaken by Plasmain. Okay? Plasmain is an active protein. The Xymogen form of Plasmain is Plasmainogen. Okay? And the conversion of Plasmainogen to Plasmain can be done by something known as a TPA. Okay? So TPA is a clot-busting drug. So like, altar plays, redder plays, the nectar plays. They work by helping you convert Plasmainogen to Plasmain. And then that Plasmain can go ahead and lice Fibrein. Okay. Now, some pathology. Again, we said if you have a factor eight's deficiency, that's immofilia A. Factor nine deficiency will say that's immofilia B. Factor eleven deficiency will say that's immofilia C. Remember, hemofilia A and B, and he inherited an excellent recessive fashion.

But hemofilia C is inherited in an onzumon recessive fashion. So you can shop in boys and girls. So if you see a grown hemofilia on your USMLA exams, think about hemofilia C. Not hemofilia A or B. Okay. Now, again, your PTTOB elevated in hemofilia A, B and C because those are part of those deficient factors eight, nine, and eleven are all a part of the intrinsic coagulation cascade. Your PTTOB normal. Okay? But in vomulibrancy disease, we said your bleeding time will be up and your PTTOB up because vomulibrancy factor acts as a protecting group for factor eight. So if you ever take any exam in the future and the bleeding time is elevated, the ptlet count is normal and the PTT is up. You should have a very, very good reason for not picking vomulibrancy disease. Okay. Now, this is kind of a unique question. What is the clotting factor deficiency that has more effect on the measured PTT and PTT value? Well, if you follow the long, when we were talking about the cascade, remember we said that there was this clotting factor that was sort of off to the side that just only came to stabilize the fiber and mesh. That's factor 13. Okay? A factor 13 deficiency will not present with elevations in PTT or PTT. Okay? And protein CNS, we've talked about what they do, they activate factors eight and five. Um, factor 12 talked about all its special roles, a factor five lighting, right? It's a problem where you have resistance of factor five to degradation by protein C. Okay?

So if factor five has a longer half life, you will potentially imagine that you have more risk of forming clots. Okay? So factor five lighting is a hyperquagulable disorder. In fact, if I'm not mistaken, this is probably the most common hyperquagulable disorder in the entire world. Okay? Now, a G02, so G20210 A mutation, basically this is a problem where you're making too much factor two. Okay? If you're making too much factor two, you're making more, you potentially form more clots. So that's also a hyperquagulable disorder. Okay? Antithromine three deficiency is also a hyperquagulable disorder because by having that deficiency of antithromine three, you do not in activate factors 10 and 2. Okay? So you have an increased risk of forming clots. Okay? Remember, people that have an 83 deficiency, they will potentially have a very minimal response to heprin administration, right? Because they have more 83 around. Or they may require larger than normal administration of heprin to get any kind of antithromine three response. And also remember that antithromine three is part of what is lost in the urine in an euphrodic syndrome. That's why a person could potentially get like thrombotic events in an euphrodic syndrome like renovin thrombosis, for example. Okay. So next slide. The differential diagnosis of eosenophilia, right? So remember, there is an endoblycepino monic or deantropolycepino monic or canadaepino monic. So whichever one floats your boat.

But let's use the antropolycep. Okay? So these were drugs. Okay? The N is for neoplasms. Okay? There are certain cancers, especially hematologic cancers like the Hodgkin's lymphomas that could actually present with eosenophilia. Because some of those like the redstoneberg cell every now and then produces interluchin five. So that can encourage differentiation of eosenophilus. Okay? The first aid can stand for allergies or atopic diseases or asthma. The other aid can stand for acute interstitial nephritis. Okay? The third aid can stand for adicens disease. Remember, that's an autoimmune destruction of the adrenal cortex. So, and then the C can stand for collagen vascular disease. Right? So like, trachstral syndrome. Although it's no longer trachstral syndrome. It's now called eosenophili granulomatosis with polyngitis. Right? So if a person has, they have like nephritic syndrome. They have asthma. And you find granulomers on like a long biopsy or kidney biopsy. Think about their trachstral syndrome. They classically have elevated eosenophils in the serum. And then the P stands for parasites. Okay? And two things I want to draw from this is one. You have a proliferation of eosenophils in the setting of parasitic or hellmynthic infection. Remember, the primary thing your eosenophils use to nuke those nasty buggers is a major basic protein. It's just one of those things you want to know for step one.

Another thing with that is we said that adicens disease, which is a low cortisol state, is associated with eosenophilia. So it should thus make sense that a high cortisol state. So let's assume you're taking glucocorticoids for some autoimmune disease. Or you have some kind of a cushion syndrome. It should be actually associated with a low eosenophil state. So high cortisol equals low eosenophilts. Low cortisol equals high eosenophilts. So just something to keep in mind. Now, from a ecological management of real quick, cell type with dense blue granules that are for skates the nucleus. That's bisophilia. That's those are your bisophilts. And bisophilia is classically associated with CML. Remember CML with your 922 translocation, where you make the BCR able tyrosine kinase receptor, also called the 922 translocation, it's like the Philadelphia chromosome business. And you could treat that by giving a matineepe, which is a tyrosine kinase inhibitor. Now, from a ecological management of CGD and osteoporosis, so remember CGD is the deficiency of any DPH oxidase. So if you have an any DPH oxidase deficiency, your respiratory burst does not work. So you have an increased risk of recurrent infections with cuttleys positive bugs. So it's an oxidative burst problem, which is a very important pathway in macrophages. osteoporosis is also a macrophage problem, but the macrophage that we are concerned about here is the osteoclast. Remember, osteoclast help you absorb both.

And the result bone buys basically like built in a wall known as a rough wood border. And then the secreted ton of acid across that rough wood border, and that acid helps you absorb both. Okay, one of the key enzymes in that process is kerbony can hydrate too. So if you have a deficiency of kerbony can hydrate too, you do not have your osteoclasts secreting acid into the rough wood border. So you have predominant activity of osteoblasts. Okay, and that's how you get brittle bone disease, osteoporosis. Okay, so why am I asking about these two things and asking about the pharmacological management? I'm trying to draw a parallel that these are primarily macrophage problems. And to treat these macrophage problems we can give something that potentially stimulates macrophages. So think of this thing as the anabolic steroid for macrophages. That's interferon gamma. Okay, interferon gamma is actually used to manage CGD and osteoporosis. And just real quick, while we're on the topic of macrophages, let's just quickly run through higher macrophages. So in the lungs we have the alveolar macrophages, some pathologists call them dust cells. If you go to the liver, we have a cool for cells with those. If you go to the placenta, we have the half-power cells, you're trying to perfect the BB against infection. If you go to bone, we have osteoclasts, we're like we already mentioned. If you go to the kidneys, we have the mesangial cells.

Remember the mesangial cells, from part of the glomerular matrix, and also from part of the extra glomerular apparatus. I mean sorry, the joxta glomerular apparatus. And then let's see. Yeah, those are the ones that come to mind right now. Okay, so next question, question 9. A 23-year-old female with no premenitocare delivers a steelborn, hydropic fetus. This is her second pregnancy, ding-ding-ding. Her first pregnancy was without complete cation. What is the hematologic diagnosis? So hopefully you're thinking about RH incompatibility. So this lady is more than likely RH negative. Her first pregnancy was probably with an RH depositive baby. So for that pregnancy to have had an RH depositive baby, let me show you potentially had an RH depositive husband. So when she saw that RH depositive fetus, she had body decided to make antibodies against the deantigen. Okay, so on the next and the first fetus, no problem. Okay, good delivery. But on the next pregnancy, those orangutie bodies against the deantigen can cross the placenta. Okay, remember, IgG is what will actually do this, right? Not IgM. IgG is the only immunoglobulin that crosses the placenta. So that IgG crosses the placenta, goes and basically causes an extravascular destruction of the babies are red cells. Okay, so if the baby has that severe anemia, the acardiocal pool will have to chronically be increased. They can go into high-up or heart failure. And that can cause like fluid buildup across the body.

Okay, so they can be born with hydrops fetalis. Okay, so that's RH incompatibility. Now, the blood groups, the blood groups, the blood groups. So we have many blood types. So there's like blood group A, there's blood group B, there's blood group AB, there's blood group O, there's some, there's a weird kind of blood group O that's called the bomb A phenotype. Okay, so basically these questions relating to blood groups on exams, they usually head scratchers for some people. So let's talk through this. So the thing is, let's see, how do I discuss this? If a person has the A antigen on their red cells, they have blood group A. Okay, if you have blood group A, then you form all the antibodies against things that are foreign. Okay, like the B antigen. Okay, so people that have blood group A have anti-B antibodies. Okay, and those people can only accept a blood from people that are type A, okay, and people that are type O. And the reason behind that is type O blood has no A or B antigen. So there's nothing on the type O blood that can be attacked by the anti-B antibodies that type A patients have. In addition, they can get type A blood because again, they don't have auto antibodies against the A antigen. They cannot get type B blood because they have auto antibodies against the type, against the B antigen. Okay, now for a patient that has type B blood, right, so they have the B antigen on the surface of the red cells.

So those patients will form anti-A antibodies because they don't have the A antigen on the red cells. And these patients can only receive type B blood again because they have no anti-B antibodies. They can also receive type O blood because again type O blood has no A or B antigen that can be attacked by the anti-A antibodies. But these patients cannot receive type A blood because they have anti-A antibodies. You can get an acute hemolytic transfusion reaction with that. Now, a patient that has type O blood has no A or B antigen. Okay, so if they have no, I guess before I jump to type O, let me talk about type AB. Okay, if you have type AB blood, you have type A and type B antigen. Okay, so a patient that has both does not form any antibodies against type A, does not have anti-A antibodies or anti-B antibodies. So they essentially have no antibodies in their cell. So these patients are very good at accepting blood from everybody because they have no anti-Body to attack anything. So they can get type A blood, they can get type B blood, they can get type AB blood, they can get type O blood, even. Okay, so these people that have a type AB phenotype are universal recipients. Okay, now if you jump to a person that has type O blood, a person that has type O blood has no A antigen or B antigen. So because they have no A antigen or B antigen, they form antibodies, they form anti-A and anti-B antibodies.

So these people cannot receive type A blood because you have hemolosis, they cannot receive type B blood because you have hemolosis. They also cannot receive type AB blood because they have antibodies against the A and B antigen. The only thing they can receive is type O blood. Okay, they can receive only type O blood. Because again type O blood has nothing that can be attacked by the anti-A and anti-B antibodies. Now, the bumbi phenotype, basically it's a kind of type O blood that is missing, so let me just simplify this way for you. It's missing the A antigen, it's missing the B antigen, it's missing the thin that makes type O blood type O blood. Okay, that's why I said that the bumbi phenotype is a type O blood subset. Okay, the thin it actually misses is something called the H antigen. Okay, but let's sort of live it at that. Okay, so let's just assume that the bumbi phenotype, you have a deficiency of the thin that makes type O blood type O. So these patients perform antibodies against the A antigen, against the B antigen, and against the thin that makes type O blood type O. Okay, so if they have anti-A, anti-B and anti-Make Me Look Like Type O blood antibodies, you can then reason that these patients with the bumbi phenotype cannot accept type A blood, type B blood, type A B blood or type O blood. Okay, they can only get blood from another person that has the bumbi phenotype, which is extremely unfortunate.

Okay, so I have basically talked about all the stuff on this slide, and remember people type O blood are universal donors, right? Because again, the red cells have no antigens on them, so there's nothing that can be... There's nothing that whatever anti-B, you have in your serum, won't do anything to type O blood. Although remember that people with the bumbi phenotype can get him olytic reactions if they get type O blood. Okay, that'll be a very unique exception that your bored exams would potentially want to test. Okay, so the final slide. So patient with a pass medical history of a male or rash and positive anti-bodies presents with a two week history of fatigue, dyspnea, and jundus. Okay, fatigue, dyspnea, and jundus. Haptoglobin and hematocrit levels are decreased. In direct bilirubin and urine, urinary nogen are increased. There's no increase in urine bilirubin. So what's the diagnosis? Okay, so this is hemolytic anemia. Okay, and given this patient's history of lupus, they potentially have an autoimmune hemolytic anemia. And for this, we'll need to do a comstest, a direct comstest. Well, if we'll talk about the comstest, let me sort of sort out for these weird findings from the early part of the question. Okay, because it, again, it's a very nice way for them to test biochem on the exam. Oh, I guess I'm a tabless and if you may. So this patient has an anemia. That's why they have the fatigue, the dyspnea, the fatigue and the dyspnea actually.

So why do they have the jundus? They have the jundus because they have an indirect hyperbidirubin anemia. So remember that indirect bilirubin is not water soluble. And if you have an increased level of indirect bilirubin in your blood, you can have jundus. Classically, when your total bilirubin levels go above two, you begin to have jundus. Okay, now why is the haptoglobin low? Because they have a hemolytic anemia. I remember hemoglobin is made of hym and globin. Globin, you break it down into amino acids. So no one really cares about that. But your hym is broken down into iron and protoprofren. The thing is that protoprofren can ultimately be converted to indirect bilirubin. So if you have a constant breakdown of your red cells, you have an increased production of a red cell breakdown product, protoprofren. And with that, you have more indirect bilirubin in the serum. Okay. Now why do they have an increase in the urine urinary bilinogen? They have an increase in urine urinary bilinogen because remember, that indirect bilirubin gets to the liver, is converted by UDP glucoronacyl transferase. Remember, that's like phase 2 metabolism to direct bilirubin, that is in fact water soluble. And then that direct bilirubin makes it way to the GI tract. And then the GI flora can convert that direct bilirubin to urinary bilinogen. Okay. That urinary bilinogen has two fates in the GI tract.

It can be converted to stercopylin that makes your stool like brown or whatever color the stool is. And then the urinary bilinogen can also be reabsorbed in interheapotic recirculation. And it can either go back to the liver or it can be converted to urinary bilin or you can keep it as urinary bilinogen and it will just show up in the urine. Okay. That's why your urine has the yellow color. So if a person has an increased production of indirect bilirubin, they will also have an increased production of direct bilirubin. So they will have an increased production of urinary bilinogen. So more urinary bilinogen will make it sweet to the urine. Okay. That's why they have an increased urine urinary bilinogen. Okay. Now, they will have no increase in urinary bilirubin because they have an indirect hyperbilarobinemia. Indirect bilirubin is not water soluble. So because it's not water soluble, it does not spill into the blood. And if it does not spill into the blood, it will not show up in your urine. But if a person had some kind of obstructive jaundice where they had a direct hyperbilarobinemia, direct bilirubin is water soluble, direct bilirubin can spill into the blood. When it spills into the blood, it can show up in the urine and make the urine look correct. Okay. So in an indirect hyperbilarobinemia, there is no increase in urinary bilirubin. But in a direct hyperbilarobinemia, there is an increase in urinary bilirubin.

And there will actually also be a decrease in urinary bilinogen because if you had a direct hyperbilarobinemia, from an obstructive cause, that direct bilirubin is not making its way to the GI tract. So if it doesn't make its way to the GI tract, you are not making any urinary bilinogen. So you won't have increased levels of urinary bilinogen in your urine. Okay. Now, again, your haptoglobin is low because haptoglobin binds up a heave. Okay. So let's talk about the comstest. Okay. We said for this person that has autoimmune hemolytic anemia, we are thinking of the direct comstest. So the thing is the direct comstest as a phenomenon is primarily associated with helping you detect the presence of antibodies against red cells. Okay. But the thing is you can do one of two things. You could say, you know what, let me try to find this patient's red cells and see if there are already autoantibodies on those red cells. That's what you're doing in the direct comstest. But if you're like, okay, let me try to see if this person's serum, not the cells. This person's serum has the nasty red cells. I mean, sorry, it has the nasty immunoglobulin that binds to the red cells. You do an indirect comstest. So let's talk about it from one by one. So how do you do a direct comstest? We said that a direct comstest helps you detect if there are antibodies already bound to a patient's red cells. Okay.

So the thing you do is that a patient, so like this patient, for example, you literally take their red cells, not their serum. Because the serum is not what we're concerned about in the direct comstest. You take their red cells, okay, and we assume that, oh, these people's red cells already have the bad immunoglobulin on the surface like IgG. Okay. So we take their red cells. If it has that bad immunoglobulin already bound to it, if we add IgM to the mix, that IgM can go and bind to the constant region of that immunoglobulin that is already pre-bound to the patient's red blood cell. Okay. And you have a glutination of red cells in that mixture. Okay. So that will be a positive direct comstest. You can use that to detect the presence of immunoglobulins against red cells that are already bound to the red cell membrane. But next part says, what is the diagnostic test that will be very helpful in preventing an acute hemolytic transfusion reaction? Well, the test you could use for this scenario, or you could also say for arraging compatibility, is the indirect comstest. So basically for this, you're not trying to check for red cells. I mean, sorry, you're not trying to check for immunoglobulins on the surface of a patient's red cells. What you're trying to do is you're trying to determine if the patient's serum contains immunoglobulin that has the potential to bind to red cells and cause hemoluses. So you're checking the serum, you're not checking the patient's red cells.

So the thing you do is you literally do like your centrifugation and all that fun stuff. Get rid of all of the patient's red cells. You're left with the patient's serum. The patient's serum is what may potentially contain immunoglobulins. So you take the patient's serum that may have immunoglobulins and you then give that patient like, I don't know, say for example you want to transuse that patient, or you're like, okay, this is the donor blood. Let me take red cells from the donor blood and toss it into the patient's serum. You toss those red cells into the patient's serum. That patient's serum, if it has antibodies against antigens on the surface of the patient's red cell, that those antibodies that are in that recipient's serum can bind to the antigens on the surface of the donor's red cells. And then when you add the combs reagent in this case, right, so you go ahead and add the IgM that can bind to the constant region of IgG for example, you then get agglotination. That'll be a positive indirect combs test, okay. So again, I'm going to repeat this again because it's kind of important and it's very confusing and many people do not get this for some reason. In a direct combs test, you don't do anything with the patient's serum. All you're concerned about is you take the patient to the recipient if you may. The patient's actual red cells that already have the immunoglobulin bound to them already, okay.

You take the patient's red cell so you're not doing anything with the serum in a direct combs test. You take the patient's red cells, it already has immunoglobulin bound and then you add combs reagent, which is usually IgM that can bind to IgG, okay. So if that IgM recognizes the constant region of IgG on the surface of the patient's red cells, you can tell that this person potentially has an autoimmune hemolytic anemia, okay. But in an indirect combs test, you are not testing the patient's red cells per se. You are testing the patient's serum, okay. So this has absolutely nothing to do with the patient's red cells, okay. You are taking the patient's serum and you're trying to ask yourself, does this patient's serum contain antibodies that have the ability to bind to red cell antigens, right. Because think about it, if you have a patient that is about to get a blood transfusion, right. You don't want to transfuse blood to a person and so do transfuse the wrong kind of blood. Like, oh, let's say a patient has type A blood, okay. And you give that patient type B blood. The anti-BNT bodies in the patient's serum would attack that type B blood and cause an acute hemolytic transfusion reaction that can actually lead to death, okay. And you usually prevent that by doing this test we're talking about and being a good clerk if you may, right. So clerical errors at the commonly cited reason for that kind of transfusion reaction.

So if a person, for example, has type A blood and you want to transfuse them, right. With type B blood, for example, and let's say you don't know the, you don't know the blood types natively. You could say, you know what, let me take some serum from this type A blood patient, okay. And take some red cells from this type B donor, okay. And put the red cells of that type B donor literally like plop them down into the serum of the type A patient, okay. The patient with the type A blood has anti-BNT bodies. So obviously we have those anti-BNT bodies in the serum that can bind to the B antigen on the red cells that have on the red cells that are coming from the donor, okay. When you have that bind in and then you add combs region, which is again usually IGM against IGG, okay. You then get agglutination, okay. So by doing that, you've said, oh, this recipe and serum actually has antibodies that have the potential to bind to antigens on the surface of the donor red cell, okay. And this test, the indirect combs test is also used with arachina incompatibility because again, you're trying to test mom serum for the antibodies of interest, the anti-D antibodies, okay. So and just real quick, wild on the topic of like IGM against IGG, I hope that reminds you of rheumatoid factor, okay. Aromatoid factor is a relatively sensitive for rheumatoid arthritis. It's IGM against IGG, okay. So that's the end of this tape. I know this tape was longer, okay.

But if you understand what we talked about in this episode, you should be like a hematology like maestro, okay. Just listen to it carefully, maybe go over it again. But if you can sort of explain this out to yourself, you'll probably be able to reason through many hematologic problems that make people scratch their heads on exams, okay. So if you have any questions or you spotted any errors in this podcast, feel free to reach out to me. The email is divine intervention podcasts at gmail.com. I wish you all the best on whatever exams you have in your future and have a wonderful week and a blessed week ahead. Thank you.

Beta-tetramers ($\beta_4$).

Transmutations are common in West Africans; they are generally considered more severe than cis mutations.

Beta-thal minor may occasionally show target cells on a peripheral smear, while iron deficiency anemia does not.

Factor XIII.

Hemophilias prolong PTT; VWD prolongs both bleeding time AND PTT, but platelet count remains normal.

Type AB+, as the patient has no anti-A or anti-B antibodies and can accept any type of blood.

Microcytic (MCV < 80), Normocytic (MCV 80–100), and Macrocytic (MCV > 100).

Hemoglobin H disease.

Abnormal Ristocitin co-factor assay (e.g., Von Willebrand Disease or Bernard-Soulier Syndrome).

Hemophilia A (Factor VIII deficiency).

DBFA: Low RBC count, normal WBC/Platelets. SDS: Low Neutrophil count, normal RBC/Platelets.

It activates Factors VIII and V, and converts fibrinogen to fibrin.

Indirect hyperbilirubinemia leads to increased urinary bilinogen; Direct hyperbilirubinemia leads to increased urinary bilirubin (and decreased urinary bilinogen).

Hemolytic anemia (due to increased red cell breakdown product, protoporphyrin).

Hemoglobin H disease.

Abnormal Ristocitin co-factor assay (e.g., Von Willebrand Disease or Bernard-Soulier Syndrome).

Hemophilia A (Factor VIII deficiency).

DBFA: Low RBC count, normal WBC/Platelets. SDS: Low Neutrophil count, normal RBC/Platelets.

It activates Factors VIII and V, and converts fibrinogen to fibrin.

Indirect hyperbilirubinemia leads to increased urinary bilinogen; Direct hyperbilirubinemia leads to increased urinary bilirubin (and decreased urinary bilinogen).

Hemolytic anemia (due to increased red cell breakdown product, protoporphyrin).