Hello, I'm Alan Docter, and please participate in this review course. My assignment is to discuss blood with you, hear my disclosures, and I've split the topic into two main areas. One has to do with red cells and oxygen transport. We'll focus on red cell disorders relevant to critical illness, how to recognize anemia intolerance, and how to use transfusion to address that issue. Then we will discuss the hemostasis, beginning with nomenclature and physiology of the coagulation system, as well as talking about pathologic clotting, bleeding, and blood product use in this context. We will not discuss pharmacologic approaches to hemostasis. Some interesting, important, actually, facts about red cells. They are, in fact, the most abundant cell in your body. About 85% of the cells in the human body are red blood cells. However, they only comprise about 7% of our body mass when dry. There are about 20 to 30 trillion red cells circulating in the average adult, and we make about 1.4 million per second, or 200 billion a day. In the course of a day, you replace about 1% of the circulating mass. In our lifetime, we'll make about 250 kilos of red cells, so obviously a relatively important tissue if we are devoting such a significant portion of our nutritional and energy budget to this process. Lifespan is about 100 to 120 days. Arteriovenous transit requires about 20 seconds when we're at rest. Obviously, that shortens when we are in a hyperdynamic or exercising state, and each red cell will travel about 400 kilometers in the 120 days of its lifespan. It's important to recognize that they have roles well beyond simple gas transport. They're crucial in regulation of regional vascular tone, and therefore, blood flow distribution. They have a major role in vascular antioxidant systems, participate in immune regulation, and the physiologic response to hypoxia. On to some fairly basic review of information that should be relatively familiar. It's important to understand the control of hemoglobin-oxygen affinity, which is confirmation-dependent. That means that the hemoglobin tetramer has two principal confirmations with differing oxygen affinities, the relaxed form or the oxygen-loaded form, our oxyhemoglobin, and what's called the tense form or the deoxygenated hemoglobin. The affinity for oxygen is about 500-fold higher in the relaxed or R form. The T-state hemoglobin is a lower energy state and stabilized by interchained electrostatic bonds. Binding oxygen imparts energy, torques the heme plane, which imposes strain on the confirmation and causes it to shift to hyphen-BR state. Hence, the issue of cooperativity arises from this thermodynamic coupling between successive oxygen binding and then promotion of oxygen affinity. This is described by the classic oxygen dissociation curve, which you are likely to see on your board exam. The x-axis is always the partial pressure of oxygen. The y-axis is always the fractional saturation of hemoglobin. Typically, there's a sigmoidal biphasic curve where above about 100-120 Torr, you've got fully saturated, relatively flat oxygen affinity. And then as you begin to deoxygenate, you begin to have relatively steeper increase in slope. And then what you can't see here is it plateaus again. This is the R-state binding curve and the T-state binding curve. This is relevant because if there were no cooperativity, you'd have this relatively sort of simple curve where you would have relatively limited amount. Here we see the oxygen gradient from lungs to tissue of about 100-20. You'd only transport about 38% of the oxygen if this curve were not cooperative, whereas you move about 66% of the loaded oxygen if it were with the cooperativity. And then if it were left shifted or just simple myoglobin, you'd only move about 7%. This at rest, the tissue PO2 is really about 40. So you're really just moving about 21%. There's this huge reserve of oxygen that's being sort of transported around and around in our circulation without effective gas exchange. So you're really only moving about 21% of the oxygen that's loaded in our lungs. And this is all just reserved for when you have to exercise or increase your oxygen consumption. And this is reflected in the venous saturation. Because obviously, this is the saturation of blood that's coming back around after circulatory transit. So red cells, so modulate oxygen affinity, hemoglobin that's free in plasma is very high, relatively fixed affinity. In red cells, hemoglobin is packed with a small molecule called 2,3-diphosphoglycerate or 2,3-DPG, which stabilizes the tense form and reduces oxygen affinity. This operates on a relatively slow time scale. And it links oxygen transport efficiency to physiologic demand. So in the presence of hypoxia or tissue ischemia or anemia, 2,3-DPG abundance increases in red cells, producing a right shift of the oxygen dissociation curve and improving the efficiency of offloading in the setting of increased consumption. This also occurs with pH and CO2. This is called the acid and CO2 Bohr effect. You should be familiar with both of these. As CO2 abundance increases, the curve further shifts right. Same things happens with pH and their synergy between these two things. So in the setting of high CO2, low pH, or as you might imagine with exercise or physiologic stress, the curve shifts even further right, and you have increase in offloading. So to present this in a little more detail, you should be familiar with the term P50, which is the partial pressure of oxygen when the saturation is 50%. So this can be found by looking for the 50 or halfway up the y-axis, follow that over to the curve and go straight down and you get the P02 at which there is 50% saturation. The normal is about upper 20s for humans. This shifts with temperature, pH, and CO2. There are two of principal effects here, the Haldane effect, which carbon dioxide binds directly to the N-terminus of hemoglobin and stabilizes T-state. That shifts things to the right, and when it comes off in the lung, it shifts it back to the left so that when red cells are traversing systemic vascular bed and pick up carbon dioxide, that every time carbon dioxide comes on, further facilitates oxygen export. And when carbon dioxide is exhaled in the lung, that facilitates oxygen capture. The Bohr effect, different, lower pH stabilizes the salt bridges and further shifts things right. There is a CO2 Bohr effect, which is different from the Haldane effect. And then there's the pH acid Bohr effect. The CO2 Bohr effect comes when carbon dioxide enters red cells, is converted into bicarbonate and chloride by carbonic anhydrase, I'm sorry, bicarbonate and proton by carbonic anhydrase. And then through a membrane protein called AE1, the proton exchange, I'm sorry, the bicarbonate exchanges for chloride. And for every CO2 that enters, you get a molecule of hydrochloric acid, which acidifies the red cell and further shifts things to the right. So right shifting means that the partial pressure needed to saturate hemoglobin is higher. Therefore, the P50 is higher and O2 affinity is lower. So it's a little confusing, but remember, right shift means lower affinity, lower affinity means a higher P50. It's logical. You need more oxygen to load 50%, you get a higher number. So acid, CO2, make the P50 go up. So a right shift would be a P50 in the mid thirties from normal. Left shifting does the opposite. And so to the left, you have a higher pH, lower CO2, lower temperature, lower DPG. HBF or fetal hemoglobin is left shifted, obviously need to capture oxygen from baby to mom. And to the right, these are all things that happen in the lung, basically. On the right, lower pH, higher CO2, higher temperature, higher DPG, that facilitates oxygen offloading. Higher P50, lower P50, left shifting, higher affinity, right shifting, lower affinity. So again, you can see when you right shift, you increase the efficiency of oxygen offloading. So we're looking at this red left shifted curve in the lung and the purple right shifted curve in the tissue and the transfer from just the blue line is 77%. The transfer of oxygen from the red to purple line is 88%. So obviously this increases transport. So here's our first mock question. P50 shifts during circulatory transit facilitate oxygen transport during perfusion of tissue under hypoxic stress. This is pretty typical for a board type question. And the correct answer here is two. When pH is high, CO2 is low, the oxygen dissociation curve shifts left, P50 goes up, oxygen offloading is enhanced. Next topic we should cover, methemoglobinemia. There are many different causes. You can have hereditary methemoglobinemia in which you have a deficiency in any DH-dependent methemoglobin reductase or you have a hemoglobin variant, HBM, on infants less than four months old. They're particularly vulnerable to this problem and GI infection or diarrhea. Enteritis can cause it. There's also exposures to various drugs and toxins that can occur at any age, but infants are more susceptible, although they're not typically seeing these antibiotics. Usually, the thing that happens is amylocreme or benzocaine spray can produce methemoglobinemia in babies. Also, there's nitrosating agents. So inhaled nitric oxide and nitroglycerin infusions can cause methemoglobinemia given over extended periods or at very high doses. This is significant because if iron is oxidized or forms met-Fe3+, or methemoglobin, it cannot bind oxygen and it also shifts the curve to the left, so increases affinity for the remaining hemes in that tetramer if they're not all oxidized. This is important to understand the relative abundance that becomes physiologically significant. Less than 15% met is asymptomatic. We normally see about 1%. Smokers, maybe 5%. 25% to 50%, you get headache, confusion, and dyspnea. More than 50%, you begin to see major signs of oxygen delivery failure. Lab findings, partial pressure of oxygen is normal. It doesn't affect the lungs. Partial pressure or saturation by pulse oximetry is low and unreliable. Interestingly, methemoglobin is misread by the pulse oximeter and what it thinks the saturation is 85% when in fact it might be quite a bit lower. You really do need to measure this with a blood gas machine, and in particular, you have to order co-oximetry. It cannot be calculated saturation as some machines do. Patients look cyanotic. One thing this has to do with cyanosis doesn't come from the percent of hemoglobin, but the absolute abundance of deoxyhemoglobin. When you've got quite a bit of met, you don't see it, but the actual total amount, you don't see the methemoglobin. That's not why people get blue. They get blue because they've got more deoxyhemoglobin circulating. You may see signs of tissue hypoxia with high lactates and low pH and so on. What do you do? Therapy is indicated when the met percent is over 30% depending on oxygen delivery reserve or in the setting of local ischemia. For example, someone who's having a stroke or has area of focal ischemia for some reason. Obviously, you begin by removing the offended agent. You should be giving oxygen, and in some cases, hyperbaric oxygen is indicated. Methylene blue will reduce the methemoglobin, but you should recognize that it will interfere. That dye will interfere with pulse oximetry, and in extreme cases, an exchange transfusion is indicated. This is just demonstrating here that the pulse oximetry, this y-axis is the relative abundance of methemoglobin. This is the perceived fraction of oxygenated hemoglobin by pulse oximetry. You can see as the methemoglobin abundance increases, the true saturation measured by oximetry goes down in a linear fashion, whereas the pulse oximetry plateaus around 85%. This is a fair warning, classic board type question. It's also possibly relevant to know that methylene blue itself is not the reducing agent. It needs to be activated by NADPH-dependent methemoglobin reductase where it's converted to glucomethylene blue and then reduces methemoglobin. That is a little detail. Question number two, methemoglobinemia is accumulation of oxidized heme iron, diminishing blood oxygen carrying capacity. Appropriate therapies may include all the following except that is sodium thiosulfate, which is a treatment for cyanide poisoning. It's not in fact sodium thiosulfate itself may in fact cause methemoglobinemia. On to the physiology of anemia, and this is highly relevant to your clinical practice and hopefully to the board exam. It's hard to know how current the exam is with, how can I put it, more updated thinking about transfusion medicine. It is important to recognize that the level of anemia or the hemoglobin alone does not determine the clinical severity of the anemia and therefore decisions to transfuse should not be based on hemoglobin alone, even though they commonly are. Why is that so? If you think for a moment, oxygen delivery system is dependent on the heart, lungs, blood, and vascular tree. Red cells are only an element and there is significant reserve in every element of the oxygen delivery system. We talked about the reserve in red cells just by right shifting the oxygen dissociation curve. There's significant compensation for increase in oxygen consumption, reduce in oxygen availability in the lung, or reduction in oxygen carrying capacity. Similarly, if there's a reduction in oxygen carrying capacity, cardiac output can be increased, the efficiency of blood flow distribution can be improved, and the loading of oxygen can be increased with hypnea. If you are able to compensate, then you can tolerate anemia better than somebody who can't compensate. For example, someone who has a defect or diminished reserve in either the lung, heart, or vascular tree, meaning problems with vascular control such as sepsis, problems with increasing cardiac output such as cardiomyopathy or congenital heart disease, or problems with oxygenation. Those patients are less tolerant of anemia than patients who are otherwise healthy. We will go through that reasoning in some detail. What are the elements of clinical significance in addition to what I was talking about? The relative magnitude of reduction in oxygen carrying capacity, the change in total blood volume. So if you are losing blood volume as well as blood cells, that's different. Obviously, your ability to increase cardiac output is preload dependent. So if you're losing blood, you can't ramp up cardiac output. The rate at which these two things occur, if they occur slowly, you can compensate better than if they occur fast. We already discussed the ability of the cardiopulmonary system to maintain delivery by improving tissue blood flow and then underlying disorders, which may or may not affect oxygen consumption rate. The findings of anemia arise from physiologic compensation with redistribution of blood flow, increasing cardiac output, or minute volume. And the causes are sort of obvious here, reduced production or increased loss from these details. So it's important to recognize that flow trumps content in determining oxygen delivery. Here you can see data from this paper that plots blood flow versus O2 delivery versus oxygen carrying capacity versus O2 delivery. And as you can see, the relationship between blood flow and oxygen delivery, regardless of oxygen carrying capacity, the correlation coefficient is 96%. Whereas the hemoglobin amount, independent of blood flow, the correlation is only 13%. Those data more or less stand for themselves. Now, this shows the oxygen dissociation curve in the setting of a 50% reduction in hemoglobin. So that's a hemoglobin of 15 versus hemoglobin of 7. And showing the amount of blood oxygen content is functional blood PO2. If you look at the oxygen dissociation and oxygen transport across a pretty typical oxygen gradient, that's how much you move when you've got 15 grams of hemoglobin. That's how much you move if you've got 7. And without accessing cardiac output at all, you compensate significantly for the 50% reduction. In fact, you can lose about a third of your hemoglobin before this is even measurable. So there's a substantial reserve in red cells for increasing oxygen transport in the setting of anemia. And this remainder here can very easily be picked up increasing cardiac output. So it is important also to recognize that stored red cells do not perform similarly to native red cells. You take cells out, put them in a bag for a month. Obviously, they'll change and they become less deformable. They have abnormal metabolism. They generate cytokines and bioreactive reagents, and they lose control of regional blood flow. So you are not doing the same thing. You do not have the same sort of physiology. If you've lost blood and you replace it with stored red cells, that hemoglobin doesn't work the same. And that's why we need to be so parsimonious with red cells. So I'm not gonna go into great detail here, but there's obviously a very significant sort of menu in selecting blood. You can have leukoreduced blood, O-negative blood, CMV-negative blood, irradiated, washed blood. So these are the principal categories with the indications here. Washed blood is very uncommonly used, but really is intended to get rid of any residual plasma. The dose obviously is, we typically give about 10 mils per kilo because it's convenient, but if you really wanna be more precise, about three mils per kilo will change the hemoglobin by about one gram per deciliter. So if you're giving 10, you can expect to change things by about two and a half grams per deciliter. Alloimmunization occurs with nearly every transfusion. Antigens will develop to disparities in minor blood groups. That is important to understand. Hemolytic reaction, you should be familiar with this. An immediate ABO-incompatible reaction is very uncommon, but can occur. You should stop the transfusion. There's some basic labs to send, and you should save the blood, call the blood bank. You might actually, more likely, see a delayed hemolytic transfusion reaction, which is in the multiply transfused patients, typically sickle cell patients, where they react to a minor blood group. This can be quite serious, particularly if there's been an exchange transfusion, and the majority of circulating red cells are donor red cells, and they are all hemolyzing. Massive transfusions, typically thought of when more than 40 mils per kilo, is administered without care to product ratio. We should be administering these blood in a balanced ratio, typically one unit of plasma platelets and for each unit of red cells, or you will see a dilutional coagulopathy. You might also see, regardless of the ratio, administered hypocalcemia from the citrate, and that is obviously treated with calcium. You should be aware of a transfusion associated with acute lung injury, which looks like ARDS. It can occur anywhere from four to 12 hours after a transfusion, and should be reported to the blood bank. TACO is transfusion-associated circulatory overload. It is sort of self-explanatory. And TRMM is transfusion-related immunomodulation, which is more of a research topic than a practical clinical one. There's also transfusion-associated graft-versus-host disease and microchimerism. This occurs in bone marrow transplant patients or in immune-compromised patients, which residual leukocytes take up life or residual stem cells lodge in the bone marrow and start to generate donor monocytes and so on. This is why we use leukoreduced or irradiated blood in such cases. There are other very unusual, simple febrile or allergic reactions, and of course there's transmission of infection. So the important thing to recognize in the sort of dozens and dozens of restrictive versus liberal trials that you're all familiar with, basically what we have come to learn is that there's almost enough data to indicate that liberal transfusion strategy, which is typically replacing blood for a hemoglobin of nine or 10, is at least, is no better than a restrictive strategy, which is usually not transfusing until the hemoglobin is seven, and in fact is beginning to approach harm. This is most obvious in patients with cardiac surgery, surprisingly, even though they have a limited ability to preserve. So anemia worsens outcome. That's unambiguous. So if you are getting cardiac surgery and you are anemic, your outcome is worse. If you have cardiac surgery and you get transfused, your outcome is worse. So people wonder, is this confounding by indication or is there actually a real problem here? And some very careful work by this group at Hopkins has demonstrated that, in fact, transfusion does not effectively treat anemia. Just to say that again, transfusion does not effectively treat anemia. So if your hemoglobin is 25 prior to surgery and you get blood, your outcome is worse. If your hemoglobin is less than 25 and you don't get blood, your outcome is worse. So as I mentioned, anemia is bad. However, if your hemoglobin is less than 25 and you do get blood, your outcome is worse. So no matter what your pre-transfusion hemoglobin is, transfusion makes it worse. So that's kind of puzzling that even, so 25, that's a hemoglobin of a little more than seven. So if you give somebody blood and they're anemic and they are getting cardiac surgery, you will increase their mortality. Something to think about. Transfusion here increases the risk of ischemic events. In patients with cardiac surgery, this is a study of 9,000 patients. Even if your nadir hematocrit is 21, the likelihood of an ischemic event goes up quite a bit. That's also surprising. Red cell transfusion during ECMO has no detectable effect upon tissue oxygenation. That's food for thought. So this is pre-transfusion venous saturation, post-transfusion venous saturation. There's no difference. So they may as well be the same. And if you also plot that as a function of pre-transfusion hematocrit, there is no change in SVO2, no change in your infrared spectroscopy, regardless of the pre-transfusion hematocrit. So all those patients you're giving blood to on ECMO, according to preset criteria, no bearing on tissue oxygenation. Transfusion increases the likelihood of death when you're bleeding. These are not patients in shock, but these are patients, adult patients with GI bleeding. Liberal transfusion increases mortality. New England Journal paper, unambiguous data. So risk of transfusion as opposed to risk of sort of serious things that might happen to you in the course of life. So you could be hit by, you're more likely to get harmed by transfusion than be in a car accident, be shot, die in a plane, so on. I thought that was an interesting plot. So I'm just sort of very briefly gonna show you that anemia tolerance, so in healthy adults who are hemagelutid can tolerate a hemoglobin down to five with zero detectable effect on oxygen delivery. So as long as you can ramp up your cardiac output you can tolerate loss of two thirds of your red cells. What does interestingly happen is oxygen consumption goes up because the cardiac output goes up. So there's an incredible amount of reserve in the oxygen delivery system. And if you give these patients blood, you do not improve oxygen delivery. If they are unable to compensate, that's a different story. So you should all be familiar with this plot here. I urge you to get the series of papers published by the Taxi Group published in Pediatric Critical Care Medicine without going into all the details. The most current recommendations for critically ill children. Obviously, if they're in hemorrhagic shock they should get blood and they should get blood in balanced ratios. If their hemoglobin is over seven and they're stable they should not get blood. There are some select cases where you should use clinical judgment. And if the hemoglobin is five to seven you should use clinical judgment. If it is less than five, you should give blood. So the recommendation is less than five no matter what, give blood. More than seven, almost no matter what, don't give blood. Between five and seven, make a judgment. The judgment should be, is your patient getting better or worse? And you should be tipping towards transfusion if your patient is getting worse. You should be tipping away from transfusion if your patient is recovering. And if they're showing signs of stable compensation for anemia, you should try to wait. And if they're showing signs of progressive loss in reserve or unstable compensation for anemia, you should give blood. So whom to transfuse? Again, transfusion is indicated to improve oxygen delivery to tissue and for no other purpose. You should remember that. It's not for really anything else. Red cell transfusion will increase O2 content. And so it's relevant, it's appropriate when O2 content is rate limiting in delivering oxygen from lungs to tissue. It is common to transfuse for triggers designed to maintain adequate reserve. However, it is important to remember that donor red cells are not the same as native red cells. Transfusions cause harm in a dose-defending fashion. So if you're giving people blood, you are harming them, and if they don't need it. So hemoglobin triggers are undergoing reset. Currently, people tend to do seven, but as I pointed out, the published guideline is five. And there is a paradigm shift to physiologic triggers. In fact, some patients should be getting transfused when their hemoglobin's nine or 10, and some patients shouldn't be getting transfused unless their hemoglobin is four or five. So switch to the coagulation system. Coagulation is basically the localized conversion of blood from a liquid to a gel. It is a horrifyingly complex process that really is not important to understand these details to practice medicine, but there's a few key items to understand. In particular, you should know about factor Xa and factor 7a. This is a key sort of moment when prothrombin's converted to thrombin, and thrombin, of course, is what converts fibrinogen to fibrin. So you really do need to understand that Xa and 7a are related to converting fibrinogen to fibrin, and of course, you need fibrin here. So things are switching from this sort of classic approach of the tissue factor pathway, which is the extrinsic to the contact activation pathway, which is the intrinsic, and the final common pathway, which is this thrombin burst. So these are two things converging here at the thrombin burst. The thrombin burst is what helps convert fibrinogen into fibrin. We now think about this as initiation, regardless of how this process gets triggered. Amplification, which now includes sort of the platelet surface, and this is the amplification process. And then propagation, where you've got the thrombin converting fibrin to, excuse me, fibrinogen to fibrin. Amplification is what used to be called the thrombin burst. So there are a number of excellent reviews if you're interested in getting, looking into this in a little more detail. So question three, the clotting cascade involves the activation of circulating enzyme precursors. And so the precursors, of course, are the factors that are circulating. In a reaction cascade, that, and I'll give you a moment to read this, and the correct answer is that it requires sufficient ionized calcium to act as a cofactor for many enzymes. That's clinically relevant, common board question, and you do need to attend to this, particularly in the setting of massive transfusion. Fibrinolysis, the opposite of clotting. This is a normal process that's part of wound healing. Here we've got plasminogen being converted to plasmin, which is the correlate for fibrinogen being converted to fibrin. And this is done endogenously by TPA and urokinase, which do this conversion. And of course, these things also happen pharmacologically. What you begin to see when this process is triggered is that fibrin is cut and we get FTPs, or fibrin degradation products, and D-dimer, as you're familiar with, is a commonly measured fibrin degradation product. It's important there's some interaction between fibrinolysis and fibrin formation, and FTPs can compete with thrombin and sort of retard the conversion of fibrinogen to fibrin. This is part of the feedback controls between these two processes, but when this gets out of hand, it can be part of the DIC pathology. And so fibrinolysis is pharmacologically inhibited by protanin and TXA, Amicar. The one that's currently in favor is TXA. You should be familiar with these drugs. So homeostasis of this system, when either one or the other is relatively dominant in us right now, obviously fibrinolysis is the dominant form. There's sort of a continual sort of slight activation of both systems at any given time. And so if fibrin is forming in healthy people, it is broken down. So we are in a sort of a fibrinolysis favored physiologic state. And when both of those get activated in parallel, you get what's called DIC, which ironically promotes bleeding. But basically you've got sort of rather than localized coagulation, disseminated, what it means is you just got widespread systemic fibrin formation and synchronous fibrinolysis. You've got widespread activation of the clotting cascade, which can, fibrin nets can create obstruction in the microcirculation. You consume coagulopathy factor and you get a consumptive coagulopathy. It can be variable and you get thrombin inhibition because as I mentioned, the FTP can feed back on this and you start to have bleeding as a consequence. This is always a secondary problem related to ischemia reperfusion, burns, trauma, rhabdomyolysis, sepsis, malignancy. Extracorporeal circuits can trigger it and it can be hyperactivated by overwhelming tissue factor release or activation of the extrinsic system. And these are the steps of this. So in terms of monitoring anticoagulation, this is sort of also another confusing and somewhat complicated area. It's important to just try to cut through a lot of the noise and recognize that these assays were developed for very specific reasons and they have narrow uses. So one is the PROTYME, which was created to monitor warfarin use. So it monitors vitamin K, dependent clotting factors. It's not that useful for much else other than maybe monitoring liver failure. It monitors the extrinsic pathway and the activated PTTs, the intrinsic pathway and can help you dealing with drugs that affect the sort of converging final common pathway. ACT is activated clotting time. It's commonly used in bypass. This is a whole blood functional assay. It's important to recognize that the ACT is not very sensitive and only useful at very, very high doses of heparin, even though it's kind of broadly used. It is, however, a functional assay. ANTI-10A is important to recognize as a pharmacokinetic assay, not a functional assay. So it measures a drug dose. So ANTI-10A measures the ability of heparin-bound AT3 to inhibit 10A. So heparin works by binding antithrombin and activating it to inhibit factor 10A, which blocks the conversion of prothrombin to thrombin. When you're measuring ANTI-10A, you're measuring heparin-bound AT3. You're not measuring anything functional. So it's important to recognize this is not a pharmacodynamic assay. It's a pharmacokinetic assay. So heparin pharmacokinetics means that you're measuring a drug amount. Pharmacodynamics means you're measuring a drug function. So ACT is a pharmacodynamic assay, PTT, dynamic assay, 10A, kinetic assay. So they are not substitutes. AT3 activity is important to understand. If you can't figure out heparin pharmacokinetics, you need to know if there's an AT3 deficiency. So if heparin is not seen to be, if there's heparin resistance, it might be because you don't have enough AT3 around. And this is, so if you've got a high heparin dose and a low ANTI-10A, or you don't seem to get the right effect, then you need to look at AT3. Thrombolastography is another functional assay that has kind of a bad rap, but it actually is quite a useful assay. It's very simple. And basically you've got blood in a cup that spins and it is triggered, a clot is triggered. And as it forms a gel, the friction on the pin that's in this rotating cup is transferred here. And you basically, you get a symmetric reading. There's nothing different between the upper and lower half. And then there's different measurements. R-time is this time here between sort of trigger and clot initiation. This typically reflects the amount of factor VIIa and tissue factor, and is a good sort of way to measure heparin or effect. The K-time is the time until the clot reaches a certain strength and can be related to the amount of fibrinogen that's available. The alpha angle, again, relates to the fiber. They point the acceleration of thrombosis. And if you've got a problem with thrombin here, this is also helps you figure out if you need to replace fibrin. The MA or G is the maximum amplitude. This has to do with platelets or platelet amount or platelet inhibitors. Also, fibrin depletion can affect the MA. And the LY30 is fibrinolysis. So this is useful if you're looking for a DIC. These are the sort of the classic sort of tag shapes, normal, hypercoagulable, hypocoagulable, meaning you've got an extended R-time and a flat angle. Hyperfibrinolysis, and you've got this steep angle here. And hypofibrinolysis where you've got this, it doesn't tail at all. So you can use this to come up with an approach to massive bleeding. And here is an example. So if you've got somebody bleeding and you've got a normal keg tracing, then you need to be looking for von Willebrand factor dysfunction, which can be acquired and bypass ECMO, or you could have just von Willebrand factor deficiency. If you've got a flat angle, then you might have low fibrinogen and that is treated with cryoprecipitate. And if you've got a low amplitude, that should be treated with platelets. And if you've got an extended R-time, then usually you need to treat this with plasma. This is assuming that you're not, you don't have, not have a patient on heparin, also can use vitamin K. And also you can make sure you should be using a protamine with the tag if you've got a patient, I'm sorry, use protamine if you got an R difference with heparinase. Here, if you've got fibrinolysis, that's treated with TXA or Amicar. And if you're hypercoagulable, and you've got a very high MA, you use aspirin or dipyridamole and use a heparin, heparinoid heparin, if you've got a very short R-time. So here's another question. DIC is a pathologic condition characterized by? And the correct answer is elevated D-dimer, thrombocytopenia, and variable PTT and PT. There's no classic, and this can be normal or elevated. Thrombophilias, there are a few congenital thrombophilias. This means your tendency to clot. This is sort of the classic sort of, sort of things that you test for with labs. You can also have acquired, which is deficiency in AT3 protein CNS. I mean, these can be congenital or acquired. The typical acquired problems for thrombophilia are ALPS. And these are the antiphospholipid antibody syndromes that can be catastrophic, and that you're looking for the lupus anticoagulant and these other antibodies that you should be searching for. Heparin-induced thrombocytopenia actually produces clotting, even though their platelet count is low, they're all activated, and there's a screen for this. And then obviously there's some other metabolic and systemic diseases associated with clotting. Bleeding, diatheses, obviously platelet dysfunction, thrombocytopenia, von Willebrand's disease. Treatment here is DD-ABP. This is important, and this should be looked for. If you've got unexplained bleeding on ECMO, by the way, you can get acquired von Willebrand's disease there. And these are the humoral causes which have sort of very simple factor replacement. Blood component therapy, obviously platelets for low platelet count, plasma, as I pointed out, if you're trying to replace a factor in cryoprecipitate, you're trying to replace fibrinogen. So thank you for your attention. I know this is virtual, but if there are any questions, please contact me at this address. I'd be delighted to speak with you and interact with any of you either by email or a call.

blood

red cells

oxygen transport

hemostasis

hemoglobin-oxygen affinity

anemia tolerance

fibrinolysis

transfusion-associated complications