Good afternoon, I'm Rhonda Kadena. I'm a neurointensivist at the Carolinas Medical Center for Atrium Health in Charlotte, North Carolina. I have no disclosures. Today I'm going to review the high-yield hematology topics as outlined in the AVPN content outline for the Neurocritical Care Boards. I'm also going to discuss some neurological complications of chemotherapy, stem cell transplantation, and CAR T therapy, as well as neurological complications of sickle cell crisis and its treatment. I will start with anemia, which is one of the most common hematological disorders we see in the ICU. Now before talking about anemia, we should first acknowledge that transfusions carry a significant risk, so the determination of the cause of anemia and understanding the goals of transfusions are important. The 2016 recommendations for the American Board of Blood Banks recommends transfusion goals of less than seven in stable, critically ill patients, and less than eight in patients with cardiovascular disease or undergoing surgery. However, these goals may not be appropriate in the neuro-ICU. Consider these cases. A 24-year-old male with severe TBI and a Lycox monitor in place which shows cerebral hypoxia, and the current hemoglobin is 8.2. A 72-year- old female who has an MCA stroke with an admission hemoglobin of 8.7. A 44-year- old female who was admitted for non-convulsive status epilepticus who has had a prolonged hospital course and a slow decline in the hemoglobin in the last check is 7.4. And a 52-year-old admitted with a subarachnoid hemorrhage who was on vasopressors for cerebral vasospasm and currently has a hemoglobin of 7.4. Now all of these meet the goals set forth by the AABB, but are they appropriate for these conditions? Keep in mind that the trials that determine the transfusion goals did not include these neurological conditions, and so one should be cautious when determining standard goals while they understand the risk of transfusions and risks of cerebral hypoxia in acute neurological conditions. Other than blood loss, which occurs in cases of hemorrhage or frequent blood draws in the ICU, or hemolysis, which we will discuss later, intrinsic anemia occurs by three mechanisms. On the right, you can see a basic structure of red cell formation. Erythropoietin is released from the kidney and travels to the bone marrow. There, with the help of iron, folic acid, and B12, erythroblasts are produced. These form reticulocytes, which then mature into erythrocytes and are released from the bone marrow. Anemia can occur if there is a decrease in erythropoietin production, as seen in renal disease, a decreased response of the bone marrow to the erythropoietin, or in bone marrow failure. This is a summary flowchart that demonstrates labs used in the workup. Anemia is split into three different types based on the volume of the red blood cells. The microcytic anemia, which is seen in states of low iron, and the thalassemias, which is poor hemoglobin production. Macrocytic, which you see on the right, which is seen in conditions of low vitamin B12 or folate, or in chronic liver disease or alcohol abuse. And normocytic, which you see in the center, which is seen in bone marrow failure and hemolytic anemias. I will now expand on hemolysis in the next slide. The major mechanisms by which hemolysis occurs include acquired conditions, such as infections and autoimmune processes, congenital conditions, and red cell destruction, such as shearing that occurs in valvular diseases. In order to understand the labs that are associated with diagnosing hemolysis, you can see the figure on the right. A lysed red blood cell releases LDH and hemoglobin, and that is taken up by haptoglobin, which comes from the liver. And that haptoglobin-hemoglobin complex is taken up by macrophages, which then releases heme and bilirubin. Now we can't talk about anemia without talking about the oxygen delivery equation, which is important to remember for all critical care boards and practical applications in the ICU. Now keep in mind that oxygen delivery to the brain is dependent on cerebral blood flow, which might be altered in some neurological conditions. Previously we discussed the transfusion goals, but considering these cerebral blood flow alterations, the standard goals may not apply in all neurological conditions. So although the transfusion requirements have not been established in all critically ill neurological patients, guidelines have been released on two conditions thus far, including a goal of greater than 8 for subarachnoid hemorrhages, at risk for vasospasm, and greater than 10 in patients with severe TBI if there is evidence of cerebral hypoxia. Coagulopathies are also a frequent occurrence that we see in the neuro-ICU, such as this patient on the left with AML and thrombocytopenia who experienced hematoma expansion after a fall, and the 91-year-old on the right who suffered a large subdural hematoma with a midline shift as a result of a fall from a standing height while he was on Coumadin for atrial fibrillation. Coagulopathies are traditionally considered to cause excessive bleeding due to factor deficiencies, inherited traits, bone marrow cancer or failure, and acquired conditions that will be discussed later. However, there are many prothrombotic coagulopathies seen here on the right that also lead to conditions seen in the neuro-ICU, including strokes and cerebral dural venous thrombosis. Now I will not discuss the coagulation cascade in detail, but in order to understand the coagulopathies, it is important to review. The intrinsic pathway that you see on the left is stimulated by platelets or vessel wall trauma and exposed endothelium, and the intrinsic pathway is stimulated by the binding of tissue factor with factor 7. The pathways have a cascade effect to activate factors, leading to downstream activation with the merging of the two pathways in the common pathway in which thrombin is formed, leading to fibrin clots. Now after this pathway is activated, there is fibrinolysis, which is simultaneously stimulated, which then ultimately leads to the breakdown of the clots. Consider this case of an otherwise healthy 31-year-old female who was brought to the emergency department with new onset seizures and two days of body aches, fever, and confusion. On arrival, her vitals demonstrate a fever with a temperature of 39.2 degrees Celsius and tachycardia of a heart rate of 115. On exam, she has withdrawal to noxious stimuli in all four extremities, and her lower extremity exam is as you see here with purpura on both legs. A CT head was done, which was negative for any acute findings, and her lab workup demonstrates anemia with a hemoglobin of 6.9, thrombocytopenia, a platelet of 20,000, acute renal failure with a creatinine of 2.1, and otherwise a normal INR, WBC, and LFT. Now this condition that we see here must be emergently recognized as TTP. Before talking about TTP, I want to first review thrombocytopenia. Now this is caused by three major mechanisms, which include decreased platelet production that might occur due to viral infections, nutritional deficiencies, bone marrow failure, or certain drugs, or other causes include increased platelet destruction or consumption, which might occur in DIC, ITP, TTP, HIT, valvular diseases, or sequestration. Now a special note that the most common drugs that we see in the neuro ICU that cause drug-induced ITP are Bactrim, vancomycin, penicillin, rifampin, ceftriaxone, and carbamazepine. The workup of thrombocytopenia, especially in patients with anemia, includes an evaluation of the peripheral smear looking for schistocytes, which are red cell fragments. In the absence of schistocytes, labs should assess for liver dysfunction and pregnancy, which could distinguish between long-standing liver disease and health. In addition, in the absence of schistocytes, the smear can also show abnormalities that are indicative of leukemia, viral infections, or nutritional deficiencies. The lack of these abnormalities on smear would require additional history and workup, which could lead to the direction of infections, autoimmune conditions, or heparin-induced thrombocytopenia, as you see in the middle section here. Now the presence of schistocytes that we see on the right should direct your attention to the presence of overactive fibrinolysis that occurs in DIC or hemolysis, which might occur in TTP or hemolytic uremic syndrome, which is discussed later. DIC is seen in many ICUs, including the neuro ICU. It is an acquired condition in which there's an excessive amount of activation of coagulation factors, which causes microthrombi that results in the consumption of the clotting factors and platelets, which could also lead to bleeding. DIC is seen here in this diagram, in which the injury leads to the activation of the intrinsic pathway, which you can see by the blue arrow pointing down, and the thrombin directs excessive clot formation, as well as the stimulation of plasminogen and fibrinolysis, therefore leading to not only the consumption of platelets and clotting factors, but also bleeding. DIC does carry a high mortality rate regardless of the cause, but it is worse with sepsis over DIC as a result of trauma. Treatment is supportive and is focused at treating the underlying cause of the DIC. Transfusion should be avoided unless in situations of life-threatening hemorrhages, and the use of heparin should also be avoided due to the bleeding risk. Thrombotic microangiopathies are life-threatening emergencies of thrombocytopenia. The two primary conditions are TTP and HUS. Now both are characterized by thrombocytopenia and microvascular thrombi, which lead to hemolytic anemia and organ damage. TTP is due to low levels of the enzyme ADAMTS or ADAMS13, and the result then is these large strands of uncleaved von Willebrand's factor that then cause endothelial damage and platelet thrombi. Now this then causes thrombocytopenia and hemolytic anemia, as well as fever, renal failure, and neurological impairments. HUS is mostly seen in children due to the Shiga toxin from E. coli after a bloody diarrhea illness. Now these patients typically present with abdominal pain, bloody diarrhea, vomiting, and fever, as well as renal failure, but they can progress to neurological symptoms of confusion, seizures, or stroke. HUS can also be atypical and complement-mediated, which clinically may be indistinguishable from TTP. Anytime thrombocytopenia is seen with schistocytic anemia, the treatment should be initiated immediately for TTP. The mortality is very high, up to about 90% and about 50% of that mortality is in the first 24 hours if untreated. The treatment involves folic acid supplementation to prevent the depletion with ongoing hemolysis, removing the abnormal antibodies, and stopping the immune process. The best treatment is the use of plasma exchange, but unfortunately mortality is still about 20% with the use of that alone. If the plasma exchange is not available, you can give FFP, but that is only a temporary solution while you're waiting for a transfer to a facility that can offer the plasma exchange. The recommendations of the International Society on Thrombosis and Hemostasis, which were released in June of 2020, also recommend corticosteroids that should be given in addition to plasma exchange, as they can reduce mortality, but they have no benefit on their own without the use of plasma exchange. You can also use immunosuppressants that are in addition to plasma exchange and steroids because it can actually prevent relapses in some patients. Here's another case of thrombocytopenia. It's a 61 year old male who was admitted with a subarachnoid hemorrhage. On hospital day two, he was started on chemical DVT prophylaxis with heparin, and at that time he was though found to be anemic with a hemoglobin of 9.0 and normal platelets 177. Now throughout the next few days, his platelets did fall, although the rest of his CBC remained stable. Some labs were sent off, which included a PF4, which the values are shown here, and an SRA that was reported as being positive. Now based on the data that I've given, it seems obvious that the patient has heparin-induced thrombocytopenia, but let's discuss what are the criteria for sending the labs, when do you do the test, and what is the treatment. HIT consists of two different syndromes. Type 1 HIT is a non-immune mediated benign condition of mild thrombocytopenia that occurs within a few days of starting heparin, but there's no progression of the disease and discontinuation of heparin is not needed. Type 2 HIT is a prothrombotic immune mediated thrombocytopenia, which is caused by antibodies to the heparin PF4 complex. When these antibodies attack this complex, it can lead to platelet activation and thrombus formation in the venous and to a lesser extent arterial systems, and this syndrome is known as heparin-induced thrombocytopenia with thrombosis or HITT. The clinical result can be limb ischemia, DVTs, PEs, strokes, myocardial infarctions, and it carries with it a mortality of up to 20%. In type 2 HIT, the onset of the thrombocytopenia is typically between 5 to 10 days of starting heparin, but it can be within 24 hours in patients that have previously had a heparin exposure due to pre-existing antibodies, and it usually resolves within 7 to 14 days of the cessation in heparin. So the treatment is removing all sources of heparin, assessing for clots, and starting an alternative anticoagulant to reduce the risk of thromboembolic events. Now these antibodies will clear over time and do not require plasma exchange. Platelet transfusions should be avoided unless in cases of life-threatening hemorrhages. The two tests we have looking for HITT include the PF4 ELISA and the SRA. The PF4 ELISA is a test looking for antibodies to the heparin PF4 complex, and this is done in a color reaction, and the more antibodies that are present, the more dense the color reaction is, and so therefore the higher the reaction or the higher number, the more specific the test is for the presence of antibodies. The SRA is a functional assay that looks for the platelet activation in patients who have the antibodies. Considering that some patients have antibodies but they are not clinically significant in the patient, this test is important in patients who have an equivocal test or that there's a high suspicion in the presence of a negative PF4 test. In order to determine which patients need to be tested for HITT, we score them on a 4T score, which includes scoring for the level of thrombocytopenia, the timing of the platelet drop, any evidence of a thrombotic condition, or any other likely cause of the thrombocytopenia. For patients who have a low probability of HITT, a PF4 needs to be sent out, and if it's negative, then HITT can be excluded. If there's an intermediate or a high probability, heparin must be stopped in those patients, and another anticoagulant started, and a PF4 is sent. If that PF4 comes back and it's negative in the intermediate patients, then HITT can be excluded. If it's positive and it shows the antibodies, or if there's a strong suspicion that still exists for HITT despite having a negative PF4 test, then the functional SRA needs to be done. And then if the functional test is negative, then HITT can be excluded. In the neuro-ICU, we commonly see bleeding complications as a result of oral anticoagulants. On the top left, this is a CT finding of an 86-year-old female who has a history of hypertension, who is on Coumadin, and we see here a spontaneous hemorrhage in the right basal ganglia, which has been exacerbated by the use of Coumadin. Below that is a 90-year-old who is on Coumadin for atrial fibrillation, who fell from a standing height, and we see an intraparenchymal hemorrhage as well as some scattered subarachnoid hemorrhage as a result of the fall and coagulopathy from the Coumadin. There is a high risk of hematoma expansion that carries with it a poor prognosis in patients on oral anticoagulants, and that can be seen as well on the photo in the right of a CT of an 87-year-old female who was on Rivaroxaban for atrial fibrillation, who ruptured an aneurysm, and you can see the subarachnoid hemorrhage on the left picture and a hematoma expansion that occurred within just a couple of hours before the patient could be reversed. I will go back to our coagulation cascade diagram to show the sites of action of the three types of oral anticoagulants. Coumadin, which is seen in black, inhibits vitamin K dependent factors of 2, 7, 9, and 10 due to the action on the vitamin K epoxide reductase enzyme. Direct thrombin inhibitors, which are seen in blue, irreversibly inhibit thrombin, and factor Xa inhibitors, seen in green, reversibly inhibit factor Xa. This table depicts the reversing options for each of the oral anticoagulants, starting with warfarin. Do not forget the vitamin K. This is the only drug that allows for long-term reversal by resupplementing the vitamin K. It does take hours before it works, so it needs to be given early on in the patient's course. The other two options are FFP, which contains all of the hemostatic factors. However, it has to be thawed and it needs to be administered in very large volumes, which leads to a delay in the reversal of the anticoagulation and thus can worsen hematoma expansion. The other option is PCCs, including three and four-factor PCCs and four-factor, which contains not only factor VII, but also protein C and protein S. For the direct thrombin inhibitors, if you have no specific antidote, you can use four-factor PCCs, but otherwise for the direct thrombin inhibitors, we have idaruzumab, and for factor Xa inhibitors, we have indexa. Neurological complications can be seen in up to 25% of those affected with sickle cell disease and range from hearing loss to seizures, strokes, intracranial hemorrhages, and coma. Sickle cell disease is due to a mutation on the hemoglobin that causes it to become sickle-shaped and rigid when deoxygenated. This leads to occlusion and end-organ ischemia, as can be seen here in this image. Now imagine the following case that presents to your neuro ICU. You have a 27-year-old male who has sickle cell disease and is presenting with acute left hemiplegia. His vital signs are stable and his CT head is negative for acute process, but his hemoglobin is 5.2. So what is the acute management of this patient? So overall, the treatment of sickle cell crises involves the treatment of pain and the cause of the sickling, including the treatment of dehydration, infection, hypoxemia. However, in emergent conditions, such as this patient with an acute ischemic stroke due to sickling, an exchange transfusion should be done emergently in order to remove the occlusive sickle cells. Neurological complications can be seen in patients receiving stem cell transplants for a variety of conditions, including leukemia and lymphoma, and can occur early or late in the course of the treatment. Early on in the treatment, the patient is prepared for the transplant by chemotherapy, which can lead to drug toxicity or press, and radiotherapy that can lead to complications related to pancytopenia and resultant coagulopathy. During the maintenance period, the patient is continued on immunosuppression, which can lead to CNS infections or PML or progressive multifocal leukoencephalopathy, and later can experience graft-versus-host disease with neurological manifestations of cerebrovascular complications, demyelination, and immune mediated encephalitis. Although overall incidence is rare, many drugs used in hematological cancers can also lead to neurological complications, and are listed here. And finally, chimeric antigen receptor, or CAR-T therapy, is a treatment used in leukemia and lymphoma, and can lead to neurological complications referred to as the immune effector cell-associated neurotoxicity syndrome, or ICANS, that occurs as a result of the cytokine release syndrome. This cytokine storm induced by the CAR-T cells may lead to seizure activity that is very difficult to control. In addition, it causes cerebral edema that can be mild, leading to encephalopathy or seizures, or severe, leading to coma and death. ICANS is reversible, and in most conditions involves supportive care such as seizure prevention and corticosteroids to reduce the edema, as well as ruling out other causes of the edema. It should be noted that the neurotoxicity can still occur after the cytokine release syndrome has completely resolved. I would like to thank you for your time today. Thank you.

high-yield hematology

neurological complications

hematological disorders

chemotherapy

stem cell transplantation

CAR T therapy