Hemostasis: Key Clinical Vignettes Overview

Hey everyone, it's Eric from Strong Medicine, and today I'll be starting to finally close out this long-standing, infrequently updated series on hemostasis. Luckily, the relevant science has not changed much in the last 7 years, with the exception of the expanding role of the DOAC. class of anticoagulants. I'm going to talk through some clinical vignettes with board-style multiple-choice questions. Today's clinical vignettes will cover common scenarios. The next and final video in the series will do the same with uncommon scenarios. The point of these vignettes and questions is primarily so you can test your recall of material covered in the series, but there will be a few bits of new information and new clinical pearls thrown in as well. For each case, I'll start with reading the short vignette. followed by the question. After each question is read, you should pause the video, read over the answer choices, commit to one in your head, and then hit play to hear the correct answer, as well as the explanation. There are five vignettes, each with four questions. Let's get started. A 35-year-old woman is scheduled for cholecystectomy for gallstones. During the preoperative evaluation, she reports a history of bleeding, after a routine tooth extraction which was severe enough to require an ER visit. She also reports excessive gum bleeding whenever she visits the dentist. Her past medical history is otherwise unremarkable. She reports that her mother has a history of heavy menstrual bleeding and frequent nosebleeds. Her exam is unremarkable. Pre-op labs show a normal CBC which includes a normal platelet count, a normal INR, and a slightly prolonged PTT. First question, which of the following tests is most likely to establish a diagnosis? So go ahead and pause the video here and not only think it over, but also commit in your head to an answer before hitting play again. The correct answer is B, the von Willebrand factor antigen and von Willebrand factor activity. Von Willebrand disease is an inherited disease resulting in either quantitatively low or qualitatively defective von Willebrand factor. This patient has the classic presentation of a mild to moderate bleeding history, family history of the same, and a normal platelet count. Some patients with von Willebrand disease have prolonged PTT, as this patient does. Testing for von Willebrand disease is unusually complicated, but the most basic tests are von Willebrand factor antigen, which measures the quantity of von Willebrand factor in the blood, and von Willebrand factor actin. activity, which measures its ability to bind platelet glycoprotein 1B. Regarding the other choices, the serotonin release assay is a test for heparin-induced thrombocytopenia, which is not suggested at all by this history. The chronic subtype of DIC, or disseminated intravascular coagulation, can have near-normal labs, but it presents with recurrent thrombosis, not recurrent bleeding. She also has no obvious risk factors for chronic DIC. which is most classically associated with malignancy. And ADAMS13 is an enzyme which breaks down von Willebrand multimers. Reduced activity of ADAMS13 causes a disease called thrombotic thrombocytopenic purpura, which primarily manifests as microvascular thrombi and hemolytic anemia, neither of which are suggested by this history or set of labs. The next question. Activity of which of the following coagulation factors is most likely to be low. The correct answer here is C, factor VIII. Von Willebrand factor, in addition to playing a role in platelet aggregation, also serves as a carrier protein for factor VIII, increasing its half-life in the circulation. So decreased von Willebrand factor means decreased factor VIII, and this is actually why the PTT is elevated in some patients with von Willebrand disease. as the PTT measures both the function of the contact activation or intrinsic pathway, where factor VIII is located, and the common pathway. It's generally recommended to check a factor VIII level at the same time as checking a von Willebrand factor antigen and activity level, that is, before the diagnosis is even confirmed, since von Willebrand disease type 2N is associated with normal von Willebrand factor and activity levels, but a very low factor VIII activity level. A diagnosis of type 1 von Willebrand disease is confirmed. Which of the following is the most appropriate next step to take in preparation for surgery? The answer is C, a desmopressin trial, also known as a DDAVP trial. This was not specifically discussed in the series before now, but shortly after the diagnosis of von Willebrand disease, it's generally recommended to check a desmopressin trial to see if a patient responds to desmopressin. Before, its use might be contemplated for surgery or other acute bleeding. Desmopressin works by promoting the release of endogenous von Willebrand factor from endothelial storage sites and is most effective in situations where patients have only a mild to moderate decrease in von Willebrand factor levels at baseline. Regarding other answers, prednisone is a glucocorticoid or steroid that is part of the initial treatment for many immune-mediated conditions. such as immune thrombocytopenia and autoimmune hemolytic anemia. However, it has no role in managing von Willebrand disease. The indications for platelet transfusions in patients with von Willebrand disease are generally similar for the general population, and prophylactically transfusing platelets when the baseline platelet count is normal would be inappropriate. And regarding choice D, it would be profoundly rare for someone's bleeding disorder to be so severe that even relatively minor surgery like a cholecystectomy would be deemed too dangerous to consider. With proper preparation and consultation with a hematologist, any additional surgical risk due to type 1 von Willebrand disease can be fully mitigated. Other types of von Willebrand disease, particularly type 3, are a different story, and a more serious risk-benefit discussion between patient, hematologist, and surgeon would need to occur. Which of the following is closest to the probability that her child shares the same bleeding disorder? Answer is B, 50%. Most cases of von Willebrand disease are classified as type 1, which is inherited in an autosomal dominant fashion. In classical genetics, when a patient has an autosomal dominant disease, the chance that any one offspring has inherited their defective copy of the relevant gene thus inheriting the disease, is 50%. 25% would be correct for autosomal recessive diseases. Though some forms of von Willebrand disease can be inherited in autosomal recessive fashion, this is uncommon. And the difference in inheritance probability between different sexes of the child is seen in X-linked diseases such as hemophilia, not von Willebrand disease. Alright, let's move on to case 2. A 24-year-old woman at 34 weeks pregnancy presents with vaginal bleeding and pelvic pain. She is diagnosed with placental abruption and obstetric emergency requiring emergent cesarean section. Immediately after delivery she develops uncontrollable uterine hemorrhage requiring peripartum hysterectomy. While still in the operating room she is oozing blood from incisions and IV lines. The remainder of exam is notable for a pulse of 140 and a blood pressure of 84 over 50. Here are her labs both two weeks ago and right now in the OR, along with normal values. Apologies for leaving off the units, they don't fit on the screen, but for the purposes of answering questions, it's more the directionality and magnitude of the change from normal that's important rather than an absolute number with a specific unit. So question one, which of the following is the most likely diagnosis? Once again, go ahead and pause the video to think it over and commit to an answer. The correct answer is C, acute disseminated intravascular coagulation or DIC. To remind you, DIC is the name given to a systemic and total dysregulation of hemostasis in which exposure to a procoagulant factor such as tissue factor or bacterial lipopolysaccharides among other things, leads to the development of widespread microthrombi. In its acute form, consumption of coagulation factors and platelets in the process of creating these microthrombi, along with fibrin split products, inhibits additional thrombus formation, leading to hemorrhage. In its chronic form, larger vessel thrombi are the more prominent problem, leading to complications like venous thromboembolism. In this particular case, even before seeing the labs, The diagnosis is suggested by the combination of acute diffuse bleeding occurring during an obstetric emergency, which along with sepsis, some malignancies, trauma, and massive hemolysis are among its most common etiologies. The diagnosis of acute DIC is confirmed by the labs, which show the classic combination of low platelets, high INR and PTT, low fibrinogen, and high D-dimer. Regarding the other answers, thrombotic thrombocytopenic purpura, or TTP, is the most common example of a thrombotic microangiopathy, characterized by, predictably, microvascular thrombi rather than bleeding. While TTP does cause low platelets, the elevated coagulation labs are not typical. Hemophilia A is an inherited deficiency in factor 8, which definitely can cause life-threatening hemorrhage during the delivery of a baby, but doesn't typically cause low platelets or high INR. Von Willebrand disease, which we just talked about extensively, is an inherited disease resulting in either quantitatively low or qualitatively defective von Willebrand factor, which also if severe enough could cause life threatening hemorrhage. However, it is typically associated with normal platelet counts and normal INR. Next question. Which of the following is the most important immediate step in treatment? This one is a little trickier, but the answer is IV fluids. While the patient will probably require A, B, and C at some point, they are all going to take time to be delivered from the blood bank, and even if already present at the bedside, they cannot be infused as rapidly as plain old fluids. Now certainly one could argue that infusion of fluids may further dilute her clotting factors and fibrinogen, but her heart and blood pressure suggests that she is on the cusp of cardiovascular collapse and death, making the improvement of her hemodynamics take priority over correction of her hemostatic derangement. Regarding the other answer choices, although I can imagine someone arguing she should not get a red cell transfusion because her hemoglobin level isn't that low, remember that when people are acutely hemorrhaging, they are hemorrhaging both red cells and plasma in equal amounts, so the concentration of hemoglobin is not immediately changed. If the patient has developed hypovolemic shock, she has probably lost a quarter to a third of her blood volume, so you should expect her hemoglobin to drop by at least that much over the next 4 to 12 hours. So she's definitely going to need more red cells. It's just that it takes more time to get them into the body than the fluids. Regarding platelets and cryoprecipitate, transfusion thresholds in DIC need to be individualized. But as a very general rule, in a patient actively bleeding, one should transfuse platelets until they are above 50 and transfuse cryoprecipitate until fibrinogen is above 100. So again, A, B, and C are all indicated here. It's just that addressing her hypotension is the most time-sensitive issue. If a blood smear were to be examined, which of the following would be most likely observed? The answer is A, schistocytes. Schistocytes are large, irregular fragments of red blood cells, which can be caused by, among other things, RBCs getting sheared into pieces by passing through fibrin strands. Diseases that classically cause schistocytes include acute DIC, as well as TTP, hemolytic uremic syndrome, and a variety of intracardiac devices such as a mechanical aortic valve. Platelet clumping is a finding whose primary relevance is that it confuses automated cell counters, resulting in artificially low reported platelet counts, a situation known as pseudothrombocytopenia, which can result in unnecessary additional testing and inappropriate treatment. Microspherocytes are what they sound like, unusually small red blood cells that are shaped like spheres rather than biconcave discs, identifiable by their lack of central pallor. They are seen in hemolytic anemia. Rouleau formation is a distractor answer that more or less has nothing to do with hemostasis, but is rather a distinctive finding in which a collection of RBCs stack on top of one another, seen most commonly in multiple myeloma. Which of the following statements about treatment of this condition is true? The answer is B. The use of antifibrinolytic meds is generally contraindicated. These are medications like aminocoproic acid and tranexamic acid. Although they may acutely inhibit some of the bleeding that patients in acute DIC experience, they also promote generalized thrombus formation, which was the initial trigger for the DIC in the first place. Regarding choice A, the goal in transfusing blood products in DIC is cessation of bleeding and restoring the patient to a safe hemoglobin level. This will happen before cell counts and coagulation tests are restored to normal. If you transfuse products until tests are normalized, you're subjecting the patient to unnecessary transfusions, exposing them to possible circulatory overload from excessive IV fluids, increasing risk of various immunologic phenomenon associated with transfusions, and wasting a valuable resource. While starting anticoagulation in high-risk situations would likely prevent the initial trigger for DIC, the risk of developing acute DIC during surgery without anticoagulation is far lower than the risk of hemorrhaging as a direct consequence of the anticoagulation. And last, treating the underlying trigger for the condition does hasten its resolution and is as important as directly addressing the coagulation derangements. Case 3. A 60-year-old man with a history of atrial fibrillation on chronic apixaban is admitted with a perforated gastric ulcer. He is given andexanet which is the reversal agent for apixaban, and is taken for emergent surgery. Perioperatively, he is started on antibiotics to treat secondary peritonitis. On hospital day number three, he is started on therapeutic doses of inoxaparin. On hospital day number seven, while he remains on inoxaparin, he has the sudden onset of pleuritic chest pain and dyspnea. On exam, his pulse is 120, blood pressure 100 over 70, respiratory rate 30. and O2 sat is 90% on 4 liters of oxygen. A CT pulmonary angiogram diagnoses a pulmonary embolism. And then we see his CBC and coagulation labs at various points during his hospitalization, which of the following is the most likely diagnosis? The answer here is D, type 2 heparin-induced thrombocytopenia or HIT. To remind you, generally speaking, HIT is exactly what the name implies, low platelet counts that occur after a patient is given heparin, including low molecular weight heparin like anoxaparin in this case. There are two types which are otherwise completely different. Type 1 is not immune mediated, the thrombocytopenia occurs within the first two days, and it has low clinical significance. Type 2 is caused by antibodies to the complex of heparin and PF4 or platelet factor IV The thrombocytopenia most typically occurs 5-10 days after heparin exposure is started, but it can happen much more quickly if the patient has already been exposed to heparin within the last 3 months. And most importantly, the clinical significance of type 2 hits is high, with patients paradoxically being at high risk of thrombosis. The pathophysiologic mechanism behind this is complex and incompletely understood. Regarding choice A, DIC, This condition is relatively common in the hospital, and it can cause acute thrombocytopenia, as this patient has, but when acute, it leads more to bleeding rather than thrombosis. While chronic DIC does lead to thrombosis, there is nothing in the patient's history to suggest this, and that wouldn't cause the low platelet count. Regarding choice B, antibiotics can certainly cause thrombocytopenia, but they are not associated with thrombosis. Now, it's certainly conceivable that the pulmonary embolism and the thrombocytopenia are completely unrelated, but it also seems relatively unlikely a patient would develop a PE while therapeutically anticoagulated with enoxaparin and with a simultaneously low platelet count. But as answer B is possible, it would be something to consider on this patient's differential diagnosis. Which of the following is the most important next step? Answer C, discontinuation of heparin. As long as the heparin is present, antibodies will be forming and the risk of recurrent thrombosis will be high. HIT type 2 carries a non-negligible mortality rate. There are multiple alternatives to giving this patient heparin and it can take a day or two to confirm the diagnosis. Given the high pretest probability of the diagnosis in this case, there is no justification for continuing heparin. Regarding choice B, the low platelet count is a downstream effect of the pathogenesis of this problem. rather than a trigger, so just increasing the platelet count won't help, and may even increase the patient's risk of subsequent thrombosis. And let's discuss choice D. First, what exactly is plasma exchange? It's similar to dialysis in that it filters the blood, but unlike dialysis which removes only ions and small molecules, plasma exchange also removes immunoglobulins like, for example, antibodies to heparin. So it would seem like this would be an effective treatment for HIT. And, you know, there are case reports in the literature of this being done when patients had a very strong indication specifically to stay on heparin. But this is highly unusual. and not relevant to this specific case. A HIT ELISA is ordered. If the test result is negative, what is the most appropriate next step? This question requires knowledge of the two general types of tests for HIT and the relative test characteristics. The ELISA is an immunoassay that detects antibodies. It has better sensitivity than specificity. Functional assays like the heparin-induced platelet aggregation test and serotonin release assay have higher specificity but are usually send-out tests, meaning it takes longer to get their results. If the ELISA is a sensitive test, you might think that a negative test would automatically rule out HIT, but it depends on the pre-test probability. With clinical experience, you may have the consult that the pre-test probability of HIT in this particular case is high enough that a negative ELISA does not rule it out, But one can also use a clinical prediction rule called the 4Ts score. If one applies that scoring system here, the patient's platelet count dropped by more than 50%, and has a nadir higher than 20 or 20,000. So that's two points. The onset was between 5 and 10 days, so another two points. Confirmed thrombosis is another two points. And because we said that the thrombocytopenia could potentially be from antibiotics, we'll give one point for the last category, indicating that there are other possible causes. So in total, this patient has a score of 7, which gives them at least a two-thirds chance of having hit. Given how serious the diagnosis is, a negative ELISA would not result in a low enough post-test probability to consider the diagnosis ruled out. So in short, you need another test. In this case, a functional assay, so the answer is choice C. Here's a diagnostic algorithm that summarizes this thought process. Back to the case for the next question, which medication is the most appropriate treatment to start at this time? The answer is A, argatriban, which is an intravenous direct thrombin inhibitor, and which, at least in the US, is the preferred acute treatment for HIT. Aspirin and clopidogrel are both antiplatelet drugs, which are not sufficient to prevent thrombosis in HIT. While restarting the patient's outpatient apixaban, as a direct factor 10a inhibitor would seem to be an appropriate choice based on mechanism of action and the DOACs are sometimes used in HIT. The evidence for the DOACs in general in cases of HIT is not currently as robust as it is for argatraban. In addition the half-life of argatraban is much shorter so for a patient like this who seems relatively ill it would be preferable to use a medication that can be rapidly turned on and off for example if he needed to go back to the OR emergently. Case 4. A 75-year-old man with a past medical history of advanced heart failure and a mechanical mitral valve replacement on chronic warfarin is diagnosed with a urinary tract infection. He is prescribed 10 days of a standard dose of Bactrim, which is one of several brand names for the combination antibiotic trimethoprim sulfamethoxazole. Seven days into his antibiotic course, he experiences several painless bloody bowel movements. He presents to the emergency room for evaluation. On exam, his pulse is 105, blood pressure 114 over 76, his jugular venous pressure is 12 centimeters, and he has several ecchymoses on his arms and legs. His labs are notable for a hemoglobin of 12, platelets 230, INR 8.6, and PTT 40. Which of the following is the most appropriate immediate treatment? The answer is A, vitamin K. Warfarin, also known as Coumadin, is the only commonly used medication in a class called vitamin K antagonists. It works by inhibiting an enzyme called vitamin K epoxide reductase, which recycles vitamin K after it's been used as a coenzyme in the post-translational modification of some clotting factors. When excessive action of warfarin is present, as indicated here by the extremely elevated INR, it results in a state of relative vitamin K deficiency, which can be overcome by simply providing more vitamin K. Regarding B, while it is possible to reverse the effects of warfarin by transfusing fresh frozen plasma, since FFP primarily contains clotting factors, the volume that would be necessary in this case would be an issue. With an INR over 8, he would probably need more than 4 units of FFP, which would be at least 1 liter of fluid. Well, that might not seem like much, FFP is a colloid fluid rather than a crystalloid like normal saline or lactate at ringers. meaning that a much greater amount of it stays within the vascular space, at least immediately after infusion. And this patient has a history of heart failure and is already starting off with a JVP of 12, which seems to indicate they may be volume overloaded to begin with. Transfusing enough FFP to normalize the INR would run the risk of causing acute heart failure and pulmonary edema. Plus, given that the patient has a mechanical heart valve and is not actively exsanguinating, It's not clear that completely normalizing the INR would even be the goal here, rather than targeting an INR in the intended therapeutic range for whatever type of valve this patient has. While recombinant factor VII is occasionally used to reverse warfarin, its extreme expense makes it reserved for conditions more life-threatening than this appears to be. In addition, it only provides one clotting factor, so it normalizes the INR while not addressing warfarin's effects. elsewhere in the coagulation cascade. Desmopressin is typically used for platelet dysfunction including von Willebrand disease and does not correct abnormalities of the coagulation cascade. If it had been listed as an answer choice, the blood product prothrombin complex concentrate would have been a reasonable answer as well since it very rapidly corrects the INR and can do so without the intravascular volume issue of FFP. and it is preferred over FFP in most circumstances of warfarin overdose when vitamin K alone is thought to be insufficient. However, prothrombin complex concentrate does have some contraindications that should be reviewed prior to administration. What would have been the most appropriate way to avoid this outcome? Choice C, closer INR monitoring during antibiotic therapy. All antibiotics... and antifungals as well, can influence warfarin's effect on the INR, in almost all cases prolonging it. This is a common enough phenomenon that increasing how frequently the INR is monitored on patients receiving both warfarin and an antimicrobial should be standard practice. Regarding choice A, reducing the dose of the antibiotic might reduce the effect on the INR, but this would not treat the underlying infection. Regarding choice B, While switching warfarin to an alternative anticoagulant might be the best option if the antibiotic therapy was expected to be for many weeks to months, by the time one crosstapers warfarin with an alternative, like onoxaparin or DOAC, this particular antibiotic course will be mostly over anyway. And for this particular patient, DOACs are not considered to be adequate anticoagulation for mechanical heart valves based on currently available data. And choice D is incorrect because a mechanical valve is considered to be one of the strongest indications for anticoagulation and entirely holding warfarin for 10 days is both dangerous and unnecessary. Where is warfarin's site of action? Warfarin acts on the vitamin K dependent coagulation factors which include prothrombin 7, 9, and 10. In addition, it also acts on the intrinsic anticoagulant factors protein C, and protein S. Which of the following is the most common mechanism by which antibiotics increase the anticoagulation effect of warfarin? The answer is C. Antibiotics reduce the number of vitamin K-producing bacteria in the gut. While the mechanism in answer A, displacing warfarin's binding to albumin, does occur, this is a very minor effect with most antibiotics. Antibiotics can also interfere with the liver's metabolism of warfarin, leading to a high INR. However, this mechanism is not among the answer choices. Among all antimicrobials, those that are most likely to cause supratherapeutic INRs for a patient on warfarin are Bactrim, Metronidazole, and the azole class of antifungals. The last case for this video on common scenarios. A 30-year-old woman is referred to hematology clinic two weeks after a stroke in which no explanation could be identified after neurological and cardiac evaluation. The patient's past medical history is otherwise notable for a second trimester miscarriage a year ago. Prior to the stroke, she was on no medications, but following the stroke, she is now on aspirin. On exam, her vitals are normal. She has neurologic deficits consistent with her stroke. and Livido reticularis is present on her legs. Relevant labs include a hemoglobin of 13, platelets mildly low at 110, INR normal at 1.0, and PTT mildly prolonged at 40. Which of the following is the most likely diagnosis? The correct answer is D. This is a classic presentation of antiphospholipid syndrome. This is an acquired hypercoagulable state caused by antibodies against phospholipids and phospholipid binding proteins. The condition primarily manifests as either recurrent thrombosis and or pregnancy-related morbidity such as miscarriage and preeclampsia. Levodarticularis is a non-specific exam finding but is commonly observed in antiphospholipid syndrome. The elevated PTT is also typical. Regarding the other choices here, polycythemia vera is a chronic myeloproliferative disorder which is characterized by increased risk of thrombosis, but the hallmark feature is increased red blood cell mass. which would be seen here on labs as an elevated hemoglobin level, which is not present. Paroxysmal nocturnal hemoglobinuria is another acquired hypercoagulable state, but it's very rare and is manifested on labs as a hemolytic anemia. And chronic DIC could theoretically cause the combination of a stroke, low platelets, and an elevated PTT. But there's nothing on her history or exam to suggest the presence of a disease like cancer that would cause this type of DIC. So chronic DIC here, it isn't impossible per se, just much less likely than antiphospholipid syndrome. Which of the following additional test results would be the strongest evidence against a diagnosis of antiphospholipid syndrome in this patient? B. The prolonged PTT corrects with a mixing study. A mixing study is performed by combining the patient's plasma with pooled normal plasma in a one-to-one ratio, and then measuring whether the initial abnormal coagulation tests normalize. If the clotting test normalizes, the patient has a factor deficiency, such as hemophilia. If the clotting test does not normalize, the patient has a factor inhibitor, as is the case with antiphospholipid syndrome. So a correction of the PTT with a mixing study would strongly argue against the suspected diagnosis here. Regarding A, reduced activity of the natural anticoagulant protein C is actually typical of the antiphospholipid syndrome and is one of the ways in which the antibodies of the syndrome are thought to cause thrombosis. C3 and C4, members of the complement cascade, are often low in antiphospholipid syndrome. And anti-cardiolipin antibodies are just one of the antibodies that can be seen in the syndrome and are not seen in every patient. Anti-beta-2-glycoprotein-1 antibodies are actually the most clinically significant. Which of the following is a true statement regarding the patient's probable antiphospholipid syndrome? Answer C. The elevated PTT is a lab artifact that does not reflect an increased risk of bleeding. This is because measurement of the PTT involves adding phospholipids to the patient's plasma to induce a fibrin clot. Regarding choices A and B, patients with antiphospholipid syndrome are at increased risk of both arterial and venous thromboses. And regarding choice D, anticoagulants, not antiplatelet drugs, are the most important meds to prevent recurrent thrombosis. And the final question of the video, antiphospholipid syndrome is most strongly associated with what other condition? The answer is A, lupus. Approximately 50% of cases of antiphospholipid syndrome are associated with other autoimmune diseases, of which lupus is the most common. Pancreatic cancer is associated with chronic DIC, as well as secondary thrombocytosis. Essential thrombocythemia is a chronic myeloproliferative syndrome with overlapping clinical features as polycythemia vera, and advanced liver disease can cause a variety of abnormalities of hemostasis, but it has no specific association with antiphospholipid syndrome. That concludes Part 1 of the Clinical Vignettes, covering some common clinical scenarios. In the next and final video in this series on hemostasis, I'll do the same with some uncommon scenarios.

Today's clinical vignettes will cover common scenarios. The next and final video in the series will do the same with uncommon scenarios. The point of these vignettes and questions is primarily so you can test your recall of material covered in the series, but there will be a few bits of new information and new clinical pearls thrown in as well. For each case, I'll start with reading the short vignette. followed by the question.

After each question is read, you should pause the video, read over the answer choices, commit to one in your head, and then hit play to hear the correct answer, as well as the explanation. There are five vignettes, each with four questions. Let's get started. A 35-year-old woman is scheduled for cholecystectomy for gallstones.

During the preoperative evaluation, she reports a history of bleeding, after a routine tooth extraction which was severe enough to require an ER visit. She also reports excessive gum bleeding whenever she visits the dentist. Her past medical history is otherwise unremarkable. She reports that her mother has a history of heavy menstrual bleeding and frequent nosebleeds.

Her exam is unremarkable. Pre-op labs show a normal CBC which includes a normal platelet count, a normal INR, and a slightly prolonged PTT. First question, which of the following tests is most likely to establish a diagnosis?

So go ahead and pause the video here and not only think it over, but also commit in your head to an answer before hitting play again. The correct answer is B, the von Willebrand factor antigen and von Willebrand factor activity. Von Willebrand disease is an inherited disease resulting in either quantitatively low or qualitatively defective von Willebrand factor.

This patient has the classic presentation of a mild to moderate bleeding history, family history of the same, and a normal platelet count. Some patients with von Willebrand disease have prolonged PTT, as this patient does. Testing for von Willebrand disease is unusually complicated, but the most basic tests are von Willebrand factor antigen, which measures the quantity of von Willebrand factor in the blood, and von Willebrand factor actin.

activity, which measures its ability to bind platelet glycoprotein 1B. Regarding the other choices, the serotonin release assay is a test for heparin-induced thrombocytopenia, which is not suggested at all by this history. The chronic subtype of DIC, or disseminated intravascular coagulation, can have near-normal labs, but it presents with recurrent thrombosis, not recurrent bleeding.

She also has no obvious risk factors for chronic DIC. which is most classically associated with malignancy. And ADAMS13 is an enzyme which breaks down von Willebrand multimers.

Reduced activity of ADAMS13 causes a disease called thrombotic thrombocytopenic purpura, which primarily manifests as microvascular thrombi and hemolytic anemia, neither of which are suggested by this history or set of labs. The next question. Activity of which of the following coagulation factors is most likely to be low. The correct answer here is C, factor VIII.

Von Willebrand factor, in addition to playing a role in platelet aggregation, also serves as a carrier protein for factor VIII, increasing its half-life in the circulation. So decreased von Willebrand factor means decreased factor VIII, and this is actually why the PTT is elevated in some patients with von Willebrand disease. as the PTT measures both the function of the contact activation or intrinsic pathway, where factor VIII is located, and the common pathway.

It's generally recommended to check a factor VIII level at the same time as checking a von Willebrand factor antigen and activity level, that is, before the diagnosis is even confirmed, since von Willebrand disease type 2N is associated with normal von Willebrand factor and activity levels, but a very low factor VIII activity level. A diagnosis of type 1 von Willebrand disease is confirmed. Which of the following is the most appropriate next step to take in preparation for surgery? The answer is C, a desmopressin trial, also known as a DDAVP trial.

This was not specifically discussed in the series before now, but shortly after the diagnosis of von Willebrand disease, it's generally recommended to check a desmopressin trial to see if a patient responds to desmopressin. Before, its use might be contemplated for surgery or other acute bleeding. Desmopressin works by promoting the release of endogenous von Willebrand factor from endothelial storage sites and is most effective in situations where patients have only a mild to moderate decrease in von Willebrand factor levels at baseline.

Regarding other answers, prednisone is a glucocorticoid or steroid that is part of the initial treatment for many immune-mediated conditions. such as immune thrombocytopenia and autoimmune hemolytic anemia. However, it has no role in managing von Willebrand disease.

The indications for platelet transfusions in patients with von Willebrand disease are generally similar for the general population, and prophylactically transfusing platelets when the baseline platelet count is normal would be inappropriate. And regarding choice D, it would be profoundly rare for someone's bleeding disorder to be so severe that even relatively minor surgery like a cholecystectomy would be deemed too dangerous to consider. With proper preparation and consultation with a hematologist, any additional surgical risk due to type 1 von Willebrand disease can be fully mitigated.

Other types of von Willebrand disease, particularly type 3, are a different story, and a more serious risk-benefit discussion between patient, hematologist, and surgeon would need to occur. Which of the following is closest to the probability that her child shares the same bleeding disorder? Answer is B, 50%. Most cases of von Willebrand disease are classified as type 1, which is inherited in an autosomal dominant fashion. In classical genetics, when a patient has an autosomal dominant disease, the chance that any one offspring has inherited their defective copy of the relevant gene thus inheriting the disease, is 50%.

25% would be correct for autosomal recessive diseases. Though some forms of von Willebrand disease can be inherited in autosomal recessive fashion, this is uncommon. And the difference in inheritance probability between different sexes of the child is seen in X-linked diseases such as hemophilia, not von Willebrand disease. Alright, let's move on to case 2. A 24-year-old woman at 34 weeks pregnancy presents with vaginal bleeding and pelvic pain.

She is diagnosed with placental abruption and obstetric emergency requiring emergent cesarean section. Immediately after delivery she develops uncontrollable uterine hemorrhage requiring peripartum hysterectomy. While still in the operating room she is oozing blood from incisions and IV lines.

The remainder of exam is notable for a pulse of 140 and a blood pressure of 84 over 50. Here are her labs both two weeks ago and right now in the OR, along with normal values. Apologies for leaving off the units, they don't fit on the screen, but for the purposes of answering questions, it's more the directionality and magnitude of the change from normal that's important rather than an absolute number with a specific unit. So question one, which of the following is the most likely diagnosis? Once again, go ahead and pause the video to think it over and commit to an answer.

The correct answer is C, acute disseminated intravascular coagulation or DIC. To remind you, DIC is the name given to a systemic and total dysregulation of hemostasis in which exposure to a procoagulant factor such as tissue factor or bacterial lipopolysaccharides among other things, leads to the development of widespread microthrombi. In its acute form, consumption of coagulation factors and platelets in the process of creating these microthrombi, along with fibrin split products, inhibits additional thrombus formation, leading to hemorrhage.

In its chronic form, larger vessel thrombi are the more prominent problem, leading to complications like venous thromboembolism. In this particular case, even before seeing the labs, The diagnosis is suggested by the combination of acute diffuse bleeding occurring during an obstetric emergency, which along with sepsis, some malignancies, trauma, and massive hemolysis are among its most common etiologies. The diagnosis of acute DIC is confirmed by the labs, which show the classic combination of low platelets, high INR and PTT, low fibrinogen, and high D-dimer. Regarding the other answers, thrombotic thrombocytopenic purpura, or TTP, is the most common example of a thrombotic microangiopathy, characterized by, predictably, microvascular thrombi rather than bleeding. While TTP does cause low platelets, the elevated coagulation labs are not typical.

Hemophilia A is an inherited deficiency in factor 8, which definitely can cause life-threatening hemorrhage during the delivery of a baby, but doesn't typically cause low platelets or high INR. Von Willebrand disease, which we just talked about extensively, is an inherited disease resulting in either quantitatively low or qualitatively defective von Willebrand factor, which also if severe enough could cause life threatening hemorrhage. However, it is typically associated with normal platelet counts and normal INR.

Next question. Which of the following is the most important immediate step in treatment? This one is a little trickier, but the answer is IV fluids. While the patient will probably require A, B, and C at some point, they are all going to take time to be delivered from the blood bank, and even if already present at the bedside, they cannot be infused as rapidly as plain old fluids. Now certainly one could argue that infusion of fluids may further dilute her clotting factors and fibrinogen, but her heart and blood pressure suggests that she is on the cusp of cardiovascular collapse and death, making the improvement of her hemodynamics take priority over correction of her hemostatic derangement.

Regarding the other answer choices, although I can imagine someone arguing she should not get a red cell transfusion because her hemoglobin level isn't that low, remember that when people are acutely hemorrhaging, they are hemorrhaging both red cells and plasma in equal amounts, so the concentration of hemoglobin is not immediately changed. If the patient has developed hypovolemic shock, she has probably lost a quarter to a third of her blood volume, so you should expect her hemoglobin to drop by at least that much over the next 4 to 12 hours. So she's definitely going to need more red cells.

It's just that it takes more time to get them into the body than the fluids. Regarding platelets and cryoprecipitate, transfusion thresholds in DIC need to be individualized. But as a very general rule, in a patient actively bleeding, one should transfuse platelets until they are above 50 and transfuse cryoprecipitate until fibrinogen is above 100. So again, A, B, and C are all indicated here.

It's just that addressing her hypotension is the most time-sensitive issue. If a blood smear were to be examined, which of the following would be most likely observed? The answer is A, schistocytes.

Schistocytes are large, irregular fragments of red blood cells, which can be caused by, among other things, RBCs getting sheared into pieces by passing through fibrin strands. Diseases that classically cause schistocytes include acute DIC, as well as TTP, hemolytic uremic syndrome, and a variety of intracardiac devices such as a mechanical aortic valve. Platelet clumping is a finding whose primary relevance is that it confuses automated cell counters, resulting in artificially low reported platelet counts, a situation known as pseudothrombocytopenia, which can result in unnecessary additional testing and inappropriate treatment.

Microspherocytes are what they sound like, unusually small red blood cells that are shaped like spheres rather than biconcave discs, identifiable by their lack of central pallor. They are seen in hemolytic anemia. Rouleau formation is a distractor answer that more or less has nothing to do with hemostasis, but is rather a distinctive finding in which a collection of RBCs stack on top of one another, seen most commonly in multiple myeloma. Which of the following statements about treatment of this condition is true? The answer is B.

The use of antifibrinolytic meds is generally contraindicated. These are medications like aminocoproic acid and tranexamic acid. Although they may acutely inhibit some of the bleeding that patients in acute DIC experience, they also promote generalized thrombus formation, which was the initial trigger for the DIC in the first place. Regarding choice A, the goal in transfusing blood products in DIC is cessation of bleeding and restoring the patient to a safe hemoglobin level. This will happen before cell counts and coagulation tests are restored to normal.

If you transfuse products until tests are normalized, you're subjecting the patient to unnecessary transfusions, exposing them to possible circulatory overload from excessive IV fluids, increasing risk of various immunologic phenomenon associated with transfusions, and wasting a valuable resource. While starting anticoagulation in high-risk situations would likely prevent the initial trigger for DIC, the risk of developing acute DIC during surgery without anticoagulation is far lower than the risk of hemorrhaging as a direct consequence of the anticoagulation. And last, treating the underlying trigger for the condition does hasten its resolution and is as important as directly addressing the coagulation derangements. Case 3. A 60-year-old man with a history of atrial fibrillation on chronic apixaban is admitted with a perforated gastric ulcer.

He is given andexanet which is the reversal agent for apixaban, and is taken for emergent surgery. Perioperatively, he is started on antibiotics to treat secondary peritonitis. On hospital day number three, he is started on therapeutic doses of inoxaparin. On hospital day number seven, while he remains on inoxaparin, he has the sudden onset of pleuritic chest pain and dyspnea. On exam, his pulse is 120, blood pressure 100 over 70, respiratory rate 30. and O2 sat is 90% on 4 liters of oxygen.

A CT pulmonary angiogram diagnoses a pulmonary embolism. And then we see his CBC and coagulation labs at various points during his hospitalization, which of the following is the most likely diagnosis? The answer here is D, type 2 heparin-induced thrombocytopenia or HIT.

To remind you, generally speaking, HIT is exactly what the name implies, low platelet counts that occur after a patient is given heparin, including low molecular weight heparin like anoxaparin in this case. There are two types which are otherwise completely different. Type 1 is not immune mediated, the thrombocytopenia occurs within the first two days, and it has low clinical significance. Type 2 is caused by antibodies to the complex of heparin and PF4 or platelet factor IV The thrombocytopenia most typically occurs 5-10 days after heparin exposure is started, but it can happen much more quickly if the patient has already been exposed to heparin within the last 3 months. And most importantly, the clinical significance of type 2 hits is high, with patients paradoxically being at high risk of thrombosis.

The pathophysiologic mechanism behind this is complex and incompletely understood. Regarding choice A, DIC, This condition is relatively common in the hospital, and it can cause acute thrombocytopenia, as this patient has, but when acute, it leads more to bleeding rather than thrombosis. While chronic DIC does lead to thrombosis, there is nothing in the patient's history to suggest this, and that wouldn't cause the low platelet count. Regarding choice B, antibiotics can certainly cause thrombocytopenia, but they are not associated with thrombosis. Now, it's certainly conceivable that the pulmonary embolism and the thrombocytopenia are completely unrelated, but it also seems relatively unlikely a patient would develop a PE while therapeutically anticoagulated with enoxaparin and with a simultaneously low platelet count.

But as answer B is possible, it would be something to consider on this patient's differential diagnosis. Which of the following is the most important next step? Answer C, discontinuation of heparin. As long as the heparin is present, antibodies will be forming and the risk of recurrent thrombosis will be high. HIT type 2 carries a non-negligible mortality rate.

There are multiple alternatives to giving this patient heparin and it can take a day or two to confirm the diagnosis. Given the high pretest probability of the diagnosis in this case, there is no justification for continuing heparin. Regarding choice B, the low platelet count is a downstream effect of the pathogenesis of this problem. rather than a trigger, so just increasing the platelet count won't help, and may even increase the patient's risk of subsequent thrombosis.

And let's discuss choice D. First, what exactly is plasma exchange? It's similar to dialysis in that it filters the blood, but unlike dialysis which removes only ions and small molecules, plasma exchange also removes immunoglobulins like, for example, antibodies to heparin. So it would seem like this would be an effective treatment for HIT. And, you know, there are case reports in the literature of this being done when patients had a very strong indication specifically to stay on heparin.

But this is highly unusual. and not relevant to this specific case. A HIT ELISA is ordered. If the test result is negative, what is the most appropriate next step? This question requires knowledge of the two general types of tests for HIT and the relative test characteristics.

The ELISA is an immunoassay that detects antibodies. It has better sensitivity than specificity. Functional assays like the heparin-induced platelet aggregation test and serotonin release assay have higher specificity but are usually send-out tests, meaning it takes longer to get their results.

If the ELISA is a sensitive test, you might think that a negative test would automatically rule out HIT, but it depends on the pre-test probability. With clinical experience, you may have the consult that the pre-test probability of HIT in this particular case is high enough that a negative ELISA does not rule it out, But one can also use a clinical prediction rule called the 4Ts score. If one applies that scoring system here, the patient's platelet count dropped by more than 50%, and has a nadir higher than 20 or 20,000. So that's two points.

The onset was between 5 and 10 days, so another two points. Confirmed thrombosis is another two points. And because we said that the thrombocytopenia could potentially be from antibiotics, we'll give one point for the last category, indicating that there are other possible causes.

So in total, this patient has a score of 7, which gives them at least a two-thirds chance of having hit. Given how serious the diagnosis is, a negative ELISA would not result in a low enough post-test probability to consider the diagnosis ruled out. So in short, you need another test. In this case, a functional assay, so the answer is choice C.

Here's a diagnostic algorithm that summarizes this thought process. Back to the case for the next question, which medication is the most appropriate treatment to start at this time? The answer is A, argatriban, which is an intravenous direct thrombin inhibitor, and which, at least in the US, is the preferred acute treatment for HIT.

Aspirin and clopidogrel are both antiplatelet drugs, which are not sufficient to prevent thrombosis in HIT. While restarting the patient's outpatient apixaban, as a direct factor 10a inhibitor would seem to be an appropriate choice based on mechanism of action and the DOACs are sometimes used in HIT. The evidence for the DOACs in general in cases of HIT is not currently as robust as it is for argatraban. In addition the half-life of argatraban is much shorter so for a patient like this who seems relatively ill it would be preferable to use a medication that can be rapidly turned on and off for example if he needed to go back to the OR emergently. Case 4. A 75-year-old man with a past medical history of advanced heart failure and a mechanical mitral valve replacement on chronic warfarin is diagnosed with a urinary tract infection.

He is prescribed 10 days of a standard dose of Bactrim, which is one of several brand names for the combination antibiotic trimethoprim sulfamethoxazole. Seven days into his antibiotic course, he experiences several painless bloody bowel movements. He presents to the emergency room for evaluation. On exam, his pulse is 105, blood pressure 114 over 76, his jugular venous pressure is 12 centimeters, and he has several ecchymoses on his arms and legs.

His labs are notable for a hemoglobin of 12, platelets 230, INR 8.6, and PTT 40. Which of the following is the most appropriate immediate treatment? The answer is A, vitamin K. Warfarin, also known as Coumadin, is the only commonly used medication in a class called vitamin K antagonists. It works by inhibiting an enzyme called vitamin K epoxide reductase, which recycles vitamin K after it's been used as a coenzyme in the post-translational modification of some clotting factors. When excessive action of warfarin is present, as indicated here by the extremely elevated INR, it results in a state of relative vitamin K deficiency, which can be overcome by simply providing more vitamin K.

Regarding B, while it is possible to reverse the effects of warfarin by transfusing fresh frozen plasma, since FFP primarily contains clotting factors, the volume that would be necessary in this case would be an issue. With an INR over 8, he would probably need more than 4 units of FFP, which would be at least 1 liter of fluid. Well, that might not seem like much, FFP is a colloid fluid rather than a crystalloid like normal saline or lactate at ringers.

meaning that a much greater amount of it stays within the vascular space, at least immediately after infusion. And this patient has a history of heart failure and is already starting off with a JVP of 12, which seems to indicate they may be volume overloaded to begin with. Transfusing enough FFP to normalize the INR would run the risk of causing acute heart failure and pulmonary edema. Plus, given that the patient has a mechanical heart valve and is not actively exsanguinating, It's not clear that completely normalizing the INR would even be the goal here, rather than targeting an INR in the intended therapeutic range for whatever type of valve this patient has.

While recombinant factor VII is occasionally used to reverse warfarin, its extreme expense makes it reserved for conditions more life-threatening than this appears to be. In addition, it only provides one clotting factor, so it normalizes the INR while not addressing warfarin's effects. elsewhere in the coagulation cascade. Desmopressin is typically used for platelet dysfunction including von Willebrand disease and does not correct abnormalities of the coagulation cascade. If it had been listed as an answer choice, the blood product prothrombin complex concentrate would have been a reasonable answer as well since it very rapidly corrects the INR and can do so without the intravascular volume issue of FFP.

and it is preferred over FFP in most circumstances of warfarin overdose when vitamin K alone is thought to be insufficient. However, prothrombin complex concentrate does have some contraindications that should be reviewed prior to administration. What would have been the most appropriate way to avoid this outcome?

Choice C, closer INR monitoring during antibiotic therapy. All antibiotics... and antifungals as well, can influence warfarin's effect on the INR, in almost all cases prolonging it.

This is a common enough phenomenon that increasing how frequently the INR is monitored on patients receiving both warfarin and an antimicrobial should be standard practice. Regarding choice A, reducing the dose of the antibiotic might reduce the effect on the INR, but this would not treat the underlying infection. Regarding choice B, While switching warfarin to an alternative anticoagulant might be the best option if the antibiotic therapy was expected to be for many weeks to months, by the time one crosstapers warfarin with an alternative, like onoxaparin or DOAC, this particular antibiotic course will be mostly over anyway.

And for this particular patient, DOACs are not considered to be adequate anticoagulation for mechanical heart valves based on currently available data. And choice D is incorrect because a mechanical valve is considered to be one of the strongest indications for anticoagulation and entirely holding warfarin for 10 days is both dangerous and unnecessary. Where is warfarin's site of action?

Warfarin acts on the vitamin K dependent coagulation factors which include prothrombin 7, 9, and 10. In addition, it also acts on the intrinsic anticoagulant factors protein C, and protein S. Which of the following is the most common mechanism by which antibiotics increase the anticoagulation effect of warfarin? The answer is C.

Antibiotics reduce the number of vitamin K-producing bacteria in the gut. While the mechanism in answer A, displacing warfarin's binding to albumin, does occur, this is a very minor effect with most antibiotics. Antibiotics can also interfere with the liver's metabolism of warfarin, leading to a high INR. However, this mechanism is not among the answer choices.

Among all antimicrobials, those that are most likely to cause supratherapeutic INRs for a patient on warfarin are Bactrim, Metronidazole, and the azole class of antifungals. The last case for this video on common scenarios. A 30-year-old woman is referred to hematology clinic two weeks after a stroke in which no explanation could be identified after neurological and cardiac evaluation. The patient's past medical history is otherwise notable for a second trimester miscarriage a year ago.

Prior to the stroke, she was on no medications, but following the stroke, she is now on aspirin. On exam, her vitals are normal. She has neurologic deficits consistent with her stroke. and Livido reticularis is present on her legs. Relevant labs include a hemoglobin of 13, platelets mildly low at 110, INR normal at 1.0, and PTT mildly prolonged at 40. Which of the following is the most likely diagnosis?

The correct answer is D. This is a classic presentation of antiphospholipid syndrome. This is an acquired hypercoagulable state caused by antibodies against phospholipids and phospholipid binding proteins. The condition primarily manifests as either recurrent thrombosis and or pregnancy-related morbidity such as miscarriage and preeclampsia. Levodarticularis is a non-specific exam finding but is commonly observed in antiphospholipid syndrome.

The elevated PTT is also typical. Regarding the other choices here, polycythemia vera is a chronic myeloproliferative disorder which is characterized by increased risk of thrombosis, but the hallmark feature is increased red blood cell mass. which would be seen here on labs as an elevated hemoglobin level, which is not present. Paroxysmal nocturnal hemoglobinuria is another acquired hypercoagulable state, but it's very rare and is manifested on labs as a hemolytic anemia.

And chronic DIC could theoretically cause the combination of a stroke, low platelets, and an elevated PTT. But there's nothing on her history or exam to suggest the presence of a disease like cancer that would cause this type of DIC. So chronic DIC here, it isn't impossible per se, just much less likely than antiphospholipid syndrome. Which of the following additional test results would be the strongest evidence against a diagnosis of antiphospholipid syndrome in this patient?

B. The prolonged PTT corrects with a mixing study. A mixing study is performed by combining the patient's plasma with pooled normal plasma in a one-to-one ratio, and then measuring whether the initial abnormal coagulation tests normalize.

If the clotting test normalizes, the patient has a factor deficiency, such as hemophilia. If the clotting test does not normalize, the patient has a factor inhibitor, as is the case with antiphospholipid syndrome. So a correction of the PTT with a mixing study would strongly argue against the suspected diagnosis here.

Regarding A, reduced activity of the natural anticoagulant protein C is actually typical of the antiphospholipid syndrome and is one of the ways in which the antibodies of the syndrome are thought to cause thrombosis. C3 and C4, members of the complement cascade, are often low in antiphospholipid syndrome. And anti-cardiolipin antibodies are just one of the antibodies that can be seen in the syndrome and are not seen in every patient.

Anti-beta-2-glycoprotein-1 antibodies are actually the most clinically significant. Which of the following is a true statement regarding the patient's probable antiphospholipid syndrome? Answer C. The elevated PTT is a lab artifact that does not reflect an increased risk of bleeding. This is because measurement of the PTT involves adding phospholipids to the patient's plasma to induce a fibrin clot. Regarding choices A and B, patients with antiphospholipid syndrome are at increased risk of both arterial and venous thromboses.

And regarding choice D, anticoagulants, not antiplatelet drugs, are the most important meds to prevent recurrent thrombosis. And the final question of the video, antiphospholipid syndrome is most strongly associated with what other condition? The answer is A, lupus.

Approximately 50% of cases of antiphospholipid syndrome are associated with other autoimmune diseases, of which lupus is the most common. Pancreatic cancer is associated with chronic DIC, as well as secondary thrombocytosis. Essential thrombocythemia is a chronic myeloproliferative syndrome with overlapping clinical features as polycythemia vera, and advanced liver disease can cause a variety of abnormalities of hemostasis, but it has no specific association with antiphospholipid syndrome. That concludes Part 1 of the Clinical Vignettes, covering some common clinical scenarios. In the next and final video in this series on hemostasis, I'll do the same with some uncommon scenarios.

Transcript for:Hemostasis: Key Clinical Vignettes Overview

Transcript for:
Hemostasis: Key Clinical Vignettes Overview