And I will be discussing bleeding and coagulation disorders in this presentation. When you approach the patient who may be bleeding, it's important to try to identify the defect. And before reaching for lab results, please pay attention to the history. Look at why they were admitted to the ICU. Is it for sepsis? Is it because they just had a major cardiovascular surgery? Also look at clinical signs to guide you to the type of bleeding. Petichiae should make you think of platelet disorders as well as mucosal bleeding. Hematomas that are found in the deep tissues should make you think of coagulation cascade disorders. Immediate bleeding after an insult suggests a platelet disorder, whereas delayed bleeding suggests a coagulation cascade disorder. The platelet plug was formed, but the coagulation cascade was not able to maintain that hemostasis. Look at other medical conditions. And when you do that, also you have to do a very thorough medication analysis to look for any drugs that may be causing platelet disorders or interfering and causing coagulation cascade problems. So when you look at testing, traditionally we look first often at platelets. To assess platelets, we look at the number and we do that by a platelet count. But in the case of a low platelet count, someone should actually look at the peripheral smear to make sure there's no platelet clumping. Platelet function is basically difficult to test for on a routine basis. Bleeding times are no longer used. When looking at the coagulation cascade, our typical tests are prothrombin time and partial thromboplastin time. Occasionally and in some circumstances in certain populations, thrombin time is also used, which detects a normal or low fibrinogen or the presence of thrombin inhibitors. So these tests would detect deficiencies. Mixing test will help you detect the presence of inhibitors versus a deficiency. And because when you have bleeding, there's usually involved fibrinolysis, the tests that are typically used are the D-dimer, which is very specific for cross-linked fibrin. Fibrin degradation products are often being phased out in many institutions, but they are also a breakdown product. It's just not completely from the clot. I wanna mention just a few words about viscoelastic assays. The TEG or thromboelastography or Rotem, which is the rotational thromboelastometry. And these are often used in patients with cardiac surgery, in trauma and in obstetrics. And these tests provide a global picture of ex vivo coagulation, both clot formation as well as clot lysis. And there's an assessment of both platelet function and fibrinolysis that we don't always get with some of our routine tests. And what this usually results in if you're using these tests is that you will end up transfusing more platelets and either cryoprecipitate or fibrinogen rather than fresh frozen plasma. There are numerous studies that correlate abnormalities of these tests with morbidity and mortality, but their superiority to guide therapy has really not been established. I included this slide of a thromboelastograph tracing for you to review in preparation for board exam so that you can look at the parameters such as the reaction time, particularly the maximum amplitude and also the life 30, which is the percent lysis 30 minutes after maximum amplitude. As you're aware, many of these thromboelastograph tracing patterns have been compared to different types of wine glasses or champagne flutes as a key to helping you identify some of the patterns. But again, at top you see normal and you'll see then a factor deficiency, hypofibrinogenemia, hyperfibrinolysis, and the last one is hypercoagulable. You'll see the maximum amplitude is much greater than normal. And this is a pattern that's actually being seen in many COVID-19 patients. Well, let's look first at thrombocytopenia. And although there's a long list of causes of thrombocytopenia, when it comes to ICU patients, at the top of the list is sepsis. And as part of that today, of course, COVID-19 infection. Disseminate intravascular coagulation can be a major cause. And then particularly in the trauma patients or surgical patients, massive blood loss. Drug induced is something we'll talk a little bit more about as well as immune thrombocytopenia and less commonly thrombotic microangiopathies may cause thrombocytopenia in your ICU patients. Drug induced thrombocytopenia may be immune or non-immune. And it's a clinical diagnosis because there are no routine tests to detect immune responses to platelets. And this typically occurs after at least a week of exposure to the drugs. The hallmark of these types of thrombocytopenia is that the platelet count is often very low, less than 20,000. And it also may be associated with a very rapid drop in platelet count. If you can identify this type of condition and stop a particular drug, the platelet count will usually normalize approximately a week after the drug discontinuation. But that will also depend on the half-life of the drug that is involved. I've put together a partial list of things that can cause drug induced thrombocytopenia that you might encounter in the ICU. Iodinated contrast media can give you a transient decrease in platelet count. Seizure medications you're probably familiar with and with thrombocytopenia. And then all the monoclonal antibodies, pick any map you want, just about all of them have been reported to cause thrombocytopenia. Above the antibiotics, vancomycin leads the list. And this is an immune thrombocytopenia. Linazolib, particularly with longer term use, and then the cephalosporins and penicillin. And a newer one on the list is the PD-L1 and the PD-1 inhibitors. Well, when you're managing thrombocytopenia that's due to defective production, such as with chemotherapy, or with non-immune destruction, the key is to treat the underlying etiology. If it's due to a drug or toxin, those should be stopped. And then the patient is supported with platelet transfusion. And the recommended approach now is to do prophylactic transfusions based on specific thresholds of platelet count. The specific threshold that you're going to use for your patient for transfusion will depend on your assessment. That includes an assessment of their risk of bleeding, and then what is a reasonable and practical platelet threshold, depending on their clinical condition. In a stable non-bleeding ICU patient, we typically would use a platelet count that's lower than 10,000. In actively bleeding patients, a threshold of 50,000 is often used. And then for neurosurgical patients or those with intracranial hemorrhage, often a platelet count of greater than 100,000 is desired. Now, platelet transfusion comes as random donor units, and that's usually about five units at a time, or a single donor pharesis unit, which is transfused as one unit for about 90 kilogram patient. So let's talk about immune thrombocytopenia. And these patients don't usually have bleeding, and they usually don't end up in the ICU unless they've had another condition such as maybe a fall and a hip fracture. Treatment of choice here is the use of steroids. Typically, we use prednisone, but in severe cases and where you need to get the platelet count up more rapidly, high-dose methylprednisolone or dexamethasone have been used. Now, for immediate procedures such as major surgery, immunoglobulin can be given. And within one to four days, the platelet count will usually increase to about 80% of the baseline. But this effect is transient and only lasts for one to two weeks. Anti-RHOD can also be used in patients who are RH positive with a spleen. Don't think you'll be asked that on a board exam question, however. Now, in immune thrombocytopenia, you wanna try to reserve platelet transfusion only in the setting of severe bleeding. If you do have to transfuse, you will have to increase the dose over what you would normally use. Now, for refractory cases of immune thrombocytopenia, you'll see rituximab being used and also thrombopoietin receptor agonist, which are used to increase the platelet production with their effects on the bone marrow. And there's three agents that are now approved. Very rarely today will you see splenectomy being utilized for immune thrombocytopenias. Let's look at our first question. The 32-year-old patient has headache, fatigue, and mild confusion. Blood pressure is 120 over 76, pulse 98, respiration's 20, temperature 99. Laboratory tests are obtained before head CT is performed. The peripheral smear is shown. The lab findings are as follows. Hematocrit, 37%, white count, 6,000. Platelet count is low at 18,000. Prothrombin time, 12.5. Partial thromboplastin time, 35. And you can see the electrolytes there, which look fairly normal. The bicarbonate is a little bit low at 20. BUN is elevated at 35. And the creatinine is 2.8. So on the next slide, we'll go to the question. So the question for this patient is, which of the following is the most appropriate intervention? One, perform a lumbar puncture. Two, transfuse platelets. Three, transfuse fresh frozen plasma or administer ceftriaxone. I'll let you think about that for just a few seconds. Well, if you recognize that this is thrombotic thrombocytopenic purpura, the correct answer would be to transfuse fresh frozen plasma. And the key features here are the low platelet count, of course, but the normal coagulation parameters. Now, when looking at that peripheral smear, there should also some clues. You have your schistocytes, the fragmented red cells. You also have very large bluish reticulocytes, indicating the bone marrow's response. And you'll notice that on this particular smear, there are absolutely no platelets whatsoever. So with thrombotic thrombocytopenic purpura, we now know the pathophysiology, which is the deficiency of von Willebrand factor cleaving metalloprotease, the ADAMTS13. And this is most commonly due to an acquired immunoglobulin G. Now, the clinical diagnosis involves thrombocytopenia and hemolytic anemia. That's really all that you need to make the diagnosis. The PENTAD that includes fever, renal dysfunction, and CNS dysfunction is only present in less than 40% of patients. Ideally, for diagnosis, what you would like to do is get an ADAMTS13 activity level. And you can now also ask for the specific autoantibodies. The treatment of TTP is plasma exchange plus fresh frozen plasma infusion. The plasma exchange removes the pathologic antibody. And the fresh frozen plasma infusion actually gives back the metalloprotease. Steroids are used to decrease the production of that pathologic antibody. And we now have another intervention, caplicizumab, that can be used in TTP. And this is called a nanobody. It's an anti-von Willebrand factor fragment. And it's approved for use with plasmapheresis. Now, it is very expensive. It costs about $270,000 to treat an episode of TTP. Rituximab has also been used in TTP, but that's an off-label use. As with other immune thrombocytopenias, you want to reserve platelet transfusions for severe bleeding. And you follow the LDH as a sign of hemolysis, as well as the platelet count and the hemoglobin. Hemolytic uremic syndrome has some similarities to TTP, but is a distinct clinical syndrome. And there's two etiologies. One associated with Shiga or Shiga-like toxin. And the other etiology is due to defective complement regulation, which can be genetic, but what we typically see in ICU patients is acquired. And that is called atypical HUS. The manifestations are prominently the thrombocytopenic microangiopathy, diarrhea, if it's associated with the Shiga toxin, and then much more common to see renal dysfunction with HUS than with TTP. If you measure ADAMTS activity levels in these patients, they will be normal or only slightly decreased. Treatment is not well-established as far Treatment is not well-established as far as definitive benefit. Plasma exchange is often done, as well as dialysis for the renal dysfunction. Transplant has also been done. But for the atypical HUS, there are now actually two anti-complement five monoclonal antibodies. And that's eculizumab and rabulizumab. Eculizumab is given every eight weeks, I'm sorry, is given every two weeks, whereas rabulizumab is given every eight weeks and may be less costly to use than the eculizumab. Well, a common immune thrombocytopenia that we deal with in the ICU on a daily basis is heparin-induced thrombocytopenia or HIT. As you know, this is due to a pathologic IgG antibody to the heparin platelet factor four complex. There are also IgA and IgM antibodies produced, but the only pathologic one is the IgG. It occurs with all heparins. And because of that, we might have to monitor the platelet count in any patient receiving heparin, usually between day four and 14, although if they've had previous exposure, they may develop the thrombocytopenia much earlier. You need to assess the risk factors and we'll go over those. But the question becomes that when should I discontinue heparin? Well, if you see the platelet counts drop below 50,000 and you're thinking about HIT, or if they decrease by 30 to 50%, you may elect to discontinue heparin while you're doing further evaluation. If they're bleeding with thrombocytopenia, but that is not common with HIT, or they develop thrombosis while on heparin, and there's a 20 to 50% incidence of thrombosis depending on the patient populations that have been reported. And that's both venous and arterial thrombosis. The risk factors associated with HIT are numerous. The highest risk is in cardiovascular and orthopedic surgery patients, but also ICU patients. It occurs more in women than in men. It occurs more commonly with unfractionated heparin than low molecular weight heparin. Also more common with therapeutic IV doses versus subcutaneous prophylactic doses and with longer duration of therapy. And the surgical literature has also recently reported an increased risk in patients with high BMIs. The diagnosis of HIT is a three-step process. The first step is to evaluate a probability score. And probably the most commonly used is the 4T score, but there's also a HIT expert probability score that was developed as a consensus among experts, but it is a little more time consuming and includes more variables. So you'll still see the 4Ts as the most commonly used. The next step is to do an antigen assay. And typically this is with ELISA. And these assays detect anti-platelet factor IV heparin complex antibodies. They are sensitive, but they have low specificity. So they're positive in over 50 to 60% of cardiac and vascular surgery patients and up to 20% of COVID-19 patients. And again, remember that although these antibodies are detected, it does not mean that these antibodies are pathologic in the sense that they cause platelet aggregation and the thrombotic events. For that determination, you need to do a functional assay for platelet aggregation. And the two studies that are typically done are heparin-induced platelet activation test and a serotonin release assay. These have high specificity for the HIT pathologic antibodies. Okay, so let's ask this question. A patient with a previous myocardial infarction and end-stage renal disease is being treated for pulmonary embolism with unfractionated heparin. On day five, the left foot is cold and no popliteal pulse is present. The platelet count has decreased from 250,000 to 100,000. After heparin is stopped, which of the following agents are used? After heparin is stopped, which of the following agents is indicated? Bundeparinux, bivalirudin, argatroban, or warfarin? So which agent would you use to treat this patient? Well, I think the best choice here is argatroban. So the management of HIT includes the use of an alternative anticoagulant for anticoagulating your patient. Argatroban is FDA approved. Bivalirudin has been used, but it is technically approved only for use in HIT in the setting of percutaneous interventions. Bundeparinux has been used, but it is not FDA approved. Warfarin is a possibility, but it can only be used once the platelet count has returned to normal, if the patient still requires anticoagulation. It is anticipated that direct oral anticoagulants may be helpful in treating this condition, but it is not FDA approved. And most of the experience that has been reported has been with ribaroxaban. Anticoagulation should be done even if the patient has no thrombosis because of the high risk of developing thrombotic events. Platelets are only transfused for severe bleeding. Now with HIT, most respond to these initial interventions, but in some refractory cases or in surgical patients where heparin use and major surgery may be needed, there have always been other options, which included IVIG and plasma exchange. I wanted to mention thrombotic thrombocytopenia in the setting of COVID-19. And this can occur with infection. And here the stimulus for the pathologic antibody is not clear. It is not heparin. It may be due to a damaged endothelium. And what it usually is is some other polyanion, some other negatively charged protein that initiates this immune response. As you know, vaccine-induced thrombotic thrombocytopenia, which we now call VIT, although in Europe it was first called VIPIT, has been associated with the adenoviral vector vaccines. And in these vaccine-induced cases, the ELISA platelet factor IV test will be positive. And you have to do the ELISA because there's other rapid antigen tests out there, but those are often negative. The functional assays will also be positive, but the key here is if you can get your lab to run them without the addition of heparin, it would prove that these are really vaccine-induced and not due to any type of heparin exposure. But again, many laboratories do not perform those assays. It is recommended to avoid heparin for anticoagulation in these circumstances, although technically heparin is not causing the complex and the activation of the antibody with the platelet factor IV. The recommended intervention is to use IVIG first. Plasma exchange has also been recommended and steroids have been used. Keep in mind that recommendations and the knowledge that we have about these COVID-19 associated thrombocytopenias is changing. So please keep that in mind and keep your ear and eyes out for more information as it develops. Okay, here we have a 30-year-old woman who presents with altered mental status, fever, and the skin lesions that you see here. There is no bleeding. The blood pressure is 110 over 58. Heart rate is 110. Respiration is 18. See the picture of her skin. Platelet count is 25,000. Her thrombin time is 20 seconds. Partial thromboplastin time is 58. Hemoglobin is 9.8. White count is elevated at 18,000. And the creatinine is 2.3. So which of the following is most appropriate after antibiotics are started? Transfusion of platelets, transfusion of FFP, transfusion of factor VII, transfusion of blood, or no transfusion? Well, I think the best answer in this circumstance is no transfusion. And this is a case actually of meningococcemia, and this is disseminated intravascular coagulation. And you'll notice the difference from TPP. Here you have a low platelet count, but you have prolongation of your coagulation cascade past the PT and the PTP. DIC is a systemic thrombohemorrhagic disorder associated with many conditions. And the list is long. Substance is often one of the most common. But I wanted to call attention to a new one that goes on our list that we see in the ICUs, and that's patients receiving CAR T therapy or the checkpoint inhibitors. And in these circumstances, DIC is associated with the cytokine release syndrome. And of course, DIC has been seen in many COVID-19 patients. There's no one single laboratory test that's definitive for DIC. So you have to put together the clinical circumstance with multiple tests. Traditionally, we typically look at the PT, PTP, which is prolonged. The platelet count is low. Fibrinogen levels are low. D-dimer is elevated. In some circumstances, thrombin time can be measured. It's not necessary. Some laboratories and institutions may monitor antithrombin levels. Because this is systemic activation and it includes both clotting and fibrinolysis, there's actually several phenotypes that have been reported and described. So in patients who have more thrombotic events, they have intravascular fibrin deposition, you'll see that your patient has thrombosis and organ failure. And this is the phenotype being described with COVID-19, but it's also seen in medical patients with DIC and multi-organ dysfunction. There's also patients that will develop more on the line of depletion of platelets and coagulation factors that's combined with defective synthesis, and they present with hemorrhage or bleeding. And this is a separate phenotype. Now, there's also an asymptomatic phenotype where there's just some abnormal lab test, but they don't have either clotting, thrombotic events, or bleeding. The treatment of DIC is to treat the underlying condition. Transfusion should be reserved for morbidity, which would be bleeding or invasive procedures. I think everybody will agree that you should not be treating laboratory results in these patients. And the blood products that you may need to use in these patients, of course, would be platelets, fresh frozen plasma, or cryoprecipitate. Now, other treatment of DIC is often promoted with using heparin, which is very controversial, but it's become a debated topic with COVID-19 patients. But if you'll look at this list, which was before COVID, you may see that they fit into some of these. So DIC with thromboses may be an indication, purpurafulminans, amniotic fluid embolism, severe persistent DIC, thrombomyelocytic leukemia. And previously, when heparin was used in the setting of DIC, low fixed dose was used, about 900 to 1,000 units of unfractionated heparin an hour. Systemic fibrinolytic inhibitors are not recommended. So let's switch and talk about hepatic failure. Of course, this is a common occurrence in the ICU, and this is a combined coagulopathy. Platelets, both production is decreased and platelet destruction may be enhanced through splenic destruction. Factor production is decreased except for factor VIII. And then the laboratory tests that we usually use are prolonged PT, but keep in mind that the PTT is often prolonged as well as liver failure progresses. In most of these patients, fibrinogen is usually adequate unless they have another condition on top of it, such as infection. The D-dimer may be normal, only slightly elevated, whereas the fibrin degradation product is elevated. The FDPs are metabolized in the liver, which is why they will be elevated where the D-dimer level is usually normal or only that mild elevated. Now, the treatment of hepatic coagulopathy is to correct vitamin K deficiency if that is present. And then if a patient has active bleeding or has need for an urgent invasive procedure, then platelets and or FFP should be transfused as necessary. Prothrombin complex concentrates have been reportedly used in hepatic coagulopathy and in hepatic transplantation, but it is not the only treatment in hepatic transplantation, but it is not approved for that indication by the FDA. If fibrinogen is low, cryoprecipitate can be used. There's also now approval of two thrombopoietin receptor agonists that can be used to increase platelets for a planned invasive procedure, and that's abitrombobag and lucidrombopag. Well, trauma and massive transfusion results in a coagulopathy that I'm sure the surgeons are very familiar with. And this is defined as non-surgical bleeding from the mucosa, serosa, the wound and vascular access sites that's not due to the surgical procedure itself. And this is a multifactorial hemostatic defect that's due to hemodilution with volume resuscitation, acidosis, particularly a pH less than 7.1, hypothermia, which is often present in trauma patients, and with the presence of disseminated intravascular coagulation, and that correlates with the injury severity and the presence of hypotension in these patients. Now, management, I'm gonna give you the simple approach because this is still a topic that's being very much debated and researched at the present time. Tranexamic acid early, within the first three hours after trauma, based on the CRASH-2 study can be administered. And then you look at the different components of the coagulation process. If there's thought to be dysfunctional or there's low platelet numbers, then you can transfuse platelets in a setting of factor depletion, which is often denoted by the prolonged PT-PTT and low fibrinogen, then FFP and cryoprecipitate or a fibrinogen concentrate can be transfused. And there has been reports of prothrombin complex concentrate used in this setting, but again, it's not FDA approved for that indication. And when, of course, the blood counts are low, red cells are usually transfused, and there's now a resurgence of interest in the use of whole blood, but there's no definitive recommendations at the current time for using whole blood. Now, we know the products to be used, and then the question becomes what ratio? And as you know, this is still a debated topic. Retrospective studies before after studies suggested better outcomes when low blood product ratios were used, but there were concerns about survival bias. And also there've been multiple ratios that have been reportedly used, platelets to red cells, FFP to red cells, or as was used in the PROPER trial, FFP to platelets to red cell. And in this randomized trial, they compared a one to one to one versus a one to one to two, with the two being the red cells. And based on their primary outcomes, there was no difference in mortality at 24 hours or 30 days. So it actually was a negative trial. Now, what they did find is that there were decreased deaths by exsanguination in the first 24 hours in the one to one to one group. And this has been translated into use definitively of the low ratio blood products for trauma patients. And that's recommended in the trauma guidelines at the present time. Now, von Willebrand disease is probably the most commonly encountered inherited coagulation disorder. And it's usually picked up coincidentally with a prolonged partial thromboplastin time. Now, if these patients need surgery, or they have some injury that results in bleeding, the approach is often to give DDABP first, and then you can actually give a von Willebrand factor substitute. So previously, we were using a factor VIII concentrate that contained high concentrations of von Willebrand factor, but there's actually now a recombinant von Willebrand factor that has no factor VIII. And the concern with factor VIII was that these high levels of factor VIII might actually precipitate thrombosis. So that means that cryoprecipitate is very seldom needed unless you don't have one of these other products to use. There's also an acquired von Willebrand, which is thought to be due to an immunoglobulin. And here, if you think that's what you're dealing with, IVIG can be considered for treating those patients to get the bleeding controlled. Well, hemophilia, A and B, factor VIII and factor IX deficiency. I think the best advice I can give you is to call your hematologist. It's also probably necessary because the blood brain's unlikely to give you the factor VIII or factor IX concentrate without their approval. The key factors to keep in mind is that in a bleeding patient, you're going to need higher dosing. And this is one of the few indications for factor VII or prothrombin complex concentrate when there's inhibitors present. But again, your hematologist can guide you in managing these patients. Well, we still see a lot of patients on warfarin, so they often come in with warfarin-related bleeding that's often due to drug interactions. And with many of these cases, not only is the prothrombin time prolonged, but also the partial thromboplastin time. If it's indicated, which means the patient is bleeding or has a need for an invasive procedure, the effects of warfarin can be reversed. Now, we've done that in the past with fresh frozen plasma, but four-factor prothrombin complex concentrate is now approved by the FDA. In addition, of course, you're going to get vitamin K. Now, one thing to keep in mind is that the advantage of the prothrombin complex concentrate is that it is easier to mix, so it's more rapidly available, and it is a lower volume than fresh frozen plasma. However, there is no evidence that one is better than the other as far as outcomes. The prothrombin complex concentrate will lower the INR more rapidly than fresh frozen plasma, but we don't have the evidence to say that that's necessarily going to improve outcomes. And if the patient still needed heparin for anticoagulation after bleeding, needs anticoagulation, then you would use heparin so that it can be turned off and also monitored very closely. Okay, so one of our problematic issues in bleeding patients is antiplatelet agents, and often the response is to give platelet transfusion. But is that the correct thing to do? Well, ex vivo studies suggest that there can be reversal of platelet dysfunction with platelet transfusion with aspirin and clopidogrel, and we have very limited in vivo studies, and these are typically volunteer studies that showed improved platelet function with clopidogrel with platelet transfusion, but didn't necessarily see the same effects with platelet transfusion when prasogrel or ticagrelor was being used. In a retrospective study where they looked at platelet transfusion in patients on antiplatelet agents, they found no decrease in rebleeding, and they actually found an increase in mortality in those who received platelet transfusion. The patients we worry about the most with antiplatelet agents are those with intracranial hemorrhage, and here I think you should be familiar with the PATCH randomized trial. It's the only randomized placebo-controlled trial in this setting where they looked at patients with intracranial hemorrhage and they transfused platelets in one group, and the other group received standard of care without platelet transfusion, and it was a surprising finding at that time that there was an increased risk for death or dependence in those who received platelet transfusion, and in another observational study, they have found that preoperative platelet transfusion did not reduce the reoperation rates for subdural hematoma, so this suggests that we should not be reaching for platelet transfusions in these patients and expect that it's going to have beneficial effects, and in fact, it may have some harmful effects. Well, there are a few other things that are being investigated for reversal of these antiplatelet agents. Oftentimes, we'll see desmopressin, EDAVP, being given, but it's never been subjected to a trial, so a trial is planned in the United Kingdom that hopefully we'll see some results from in the next few years. There's also work going on with the monoclonal antibody fragment for Ticagrelor, and it's been tested in volunteers and really has some remarkable results as far as improving platelet function, but of course, that hasn't come to clinical use yet. You may also see reports of using hemoperfusion, and these, again, have been done in vitro and have shown that, yes, they can remove rivaroxaban and Ticagrelor, but they have not been evaluated in the clinical setting. Now, let's look at bleeding with dabigatran, a thrombin inhibitor. One of the things we always want to know with these agents, is the bleeding due to the dabigatran or is it due to something else, such as an injury? So here, the partial thromboplastin time and the thrombin time may be prolonged, which reflects qualitatively the effect of the dabigatran. It's not quantitative at all. So for treatment, we have erizizumab, which is FDA approved, and it's usually given as one dose, but there's quite a few reports now suggesting that repeat dosing may be needed, particularly in patients with renal dysfunction, where that probably the half-life of the dabigatran is increased and results in continued effect. Now, one of the things, of course, that to be concerned about is cost. And a recent survey found that this monoclonal antibody was only available in about 60% of hospitals. It was available in about 95% of trauma centers. So if you don't have this accessible, then you can use prothrombin complex concentrate, even though that does not have an FDA indication. The dabigatran is removed by dialysis, so that could be another possible intervention. What you shouldn't do is give FFP or Factor VII. It has no effect and is really a waste of product. So the last thing we're gonna talk about, I think this last slide, is bleeding with Factor Xa inhibitors, which are becoming very common in our patients. So again, we wanna know, are the agents active in the blood? Do they have any effect going on? So if you have the ability, this is a great opportunity to check your anti-TIN-A activity. Now, many of these inhibitors will also prolong the prothrombin time, but apixaban may not prolong the prothrombin time. So that's a little variable. These drugs are not dialyzable. You're familiar with the approval of Andexanet, which was approved for rivaroxaban and apixaban reversal. And this is a genetically modified Factor X decoy protein. And in the clinical report of the trial, and keep in mind, this was an open-label trial. There was no control group. They achieved hemostasis in about 82%. However, there was about a 10% incidence of thromboembolic and ischemic events. And in reports subsequent to the approval, some are even higher, more than 10% incidence of thrombosis. Now, Andexanet costs about, the high dose, about $50,000. And again, a survey of hospital availability found that only about 20% of hospitals had this available, and 23 to 36% of trauma centers. So again, when you don't have Andexanet available, you can also consider prothrombin complex concentrate or the factor VIII inhibiting bypass agent. And again, in many hospitals, protocols use one of these products first before going to Andexanet. Now, the other agent that we've been waiting for, seroparentag, I don't know if that's how to pronounce it. It used to be called eripazine, which was easier. And it's still in clinical trial and I checked and I did not find any update on that. So it's still in clinical trial and hopefully we'll see more about that. But it should be much easier and much less expensive. And it will be useful for all the factor X, fundoparanox and even heparin potentially and low molecular weight heparin. I'll stop there and I appreciate you listening to the presentation. Thank you.

bleeding disorders

coagulation disorders

underlying defect

platelet count

prothrombin time

D-dimer

thromboelastography

specific disorders