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Time Stamps

  • 00:20 The game of medical Twenty Questions
  • 04:37 Case introduction
  • 05:50 The CoreIM team attempts to solve the case
  • 15:36 The discussant’s diagnostic schema for abnormal bleeding
  • 23:37 Primary versus secondary hemostasis
  • 30:33 The pathology report
  • 37:38 Criteria for the final diagnosis
  • 38:46 Dissecting a diagnostic coup
  • 49:42 Conclusion

Show Notes

  1. Medical knowledge is necessary, but alone it is insufficient to ensure diagnostic success. Rather, this knowledge must also be structured in a way that facilitates its retrieval during the diagnostic process.
  2. A diagnostic schema is a mental framework that a clinician uses to organize their knowledge about a defined problem. (The term “schema” originates from the Greek word for “form” or “shape”.)
    • The use of a schema allows a clinician to rapidly and efficiently narrow the “problem space” within which they must search for a diagnosis.
    • Schema not only enable better utilization of existing knowledge, but serve as a framework for learning new knowledge.
    • The use of diagnostic schema is a distinctive feature of expert clinical reasoning, but it has not been conclusively proven whether or not explicitly teaching schema to trainees leads to higher rates of diagnostic success.
    • Almost everyone inherits from medical training a collection of somewhat generic schemata for basic problems like AKI and hypercalcemia. But with experience, awareness of context, and deeper understanding of pathophysiology, the schemata of an expert clinician can become highly personalized, and consequently much more powerful.
  3. An example of a diagnostic schema for abnormal bleeding (as modeled by the episode’s discussant):
    • Is the bleeding history consistent with the delayed presentation of a congenital bleeding disorder, or with an acquired bleeding disorder?
    • Does the temporal pattern of bleeding suggest a problem with primary hemostasis (which typically causes immediate or early-onset bleeding after trauma), or with secondary hemostasis (which typically causes delayed and/or recurrent bleeding)?
    • Is the source of the problem the platelets, the coagulation cascade, or the soft tissue and/or vascular structures?
    • If a platelet problem, is it a quantitative or a qualitative platelet defect? If a coagulopathy, is it due to a factor deficiency or the presence of an inhibitor?
  4. A diagnosis of AL amyloidosis requires that four criteria be met (according to the International Myeloma Working Group):
    • Positive amyloid staining by Congo Red on a tissue sample (organ biopsy, fat aspirate, bone marrow biopsy).
    • Proof the amyloid deposits are derived from light chain immunoglobulins.
    • Presence of an amyloid-related syndrome (e.g. cardiomyopathy, nephropathy, hepatic infiltration, etc.).
    • Evidence of a monoclonal plasma cell disorder (e.g. serum or urine paraproteinemia, bone marrow biopsy).
  5. Systemic amyloidosis can produce abnormal bleeding through a number of mechanisms:
    • The paraproteins can deposit within blood vessel walls, leading to vascular fragility.
    • Amyloid fibrils can adsorb coagulation factors, particularly factor X, leading to a coagulopathy.
    • Amyloid fibrils can adsorb von Willebrand factor, leading to an acquired von Willebrand disease.

Transcript

[Not exact but at least similar to the audio if you want to follow along!]

JOHN: Hey Cindy… Have you ever listened to that old game show Twenty Questions?
CINDY: Twenty what?
AUDIO CLIP: “Is it animal or mineral? Is it a living American man? Did I hear it at the opera? Yes, everyone is playing Twenty Questions!” [Applause]
JOHN: You probably know how the game works. It’s been around for ages, although it was this radio show in the 1940s that really popularized it. The setup was that listeners write in with an object — it could be a thing, a place, a person, real, fictional, whatever. And a panel of experts would try to guess the object just by asking yes-or-no questions. And some of these questions are… better than others.
AUDIO CLIP: “Is it ordinarily used in the home?” “Yes, they have them in every home. How they’re used in every home I’m not going to comment on. But they have them in every home.”

“Does it have moving parts?” “Not this thing itself, no, I wouldn’t say so.”

“Is it normally to be found in the kitchen?” “I guess they have them in the kitchen. They’re not as interesting there as they are in other places.” [Laughter]

“Could I see my mother-in-law in it?” [Laughter] “Well I don’t know your mode of life; I rather hope not!” [Laughter] That’s nine questions now…

JOHN: So the audience is laughing here because the object in this case, is a keyhole. But that last mother-in-law misfire aside, if you listen to enough of these clips, the questioners are actually quite good. It’s the same panel of five people from episode to episode, and they really do become experts at it. The vast majority of the time, someone gets the answer, and usually without needing anywhere close to all twenty questions.
AUDIO CLIP: “Bobby?” “Is it nothing that is surrounding by something, rather than something solid?”

“Yes…” “Keyhole!” [Shouts and applause]

JOHN: So I’ll tell you what listening to this game show reminds me of. A few years ago I was at SHM and I was watching Gurpreet Dhaliwal, the famed diagnostician from UCSF. And he was solving a case in front of a live audience. And he concludes “I believe this is leptospirosis” — and of course, he’s right, the leptospirosis serologies come back positive. And I remember hearing that exact same kind of applause — that mixture of astonishment and wonder.
JOHN: It’s not coincidental; there really are a lot of similarities, I think, between what happens in this game and what we do as diagnosticians. Think about it. When we first meet a patient they could have anything, one or several of the thousands of diseases of the human body. And our job is to gather information, and use it to accurately and efficiently winnow that list to just one, or at most a couple of different possibilities that we can directly then test for and/or treat. The major difference, thankfully, is that there isn’t a limit to the number of questions we can ask.
CINDY: But there is! If you think about it, every question has a cost. It consumes your time. It consumes the patient’s energy and patience. (Sometimes I feel the more questions I ask, the less my patients trust me). Asking the wrong questions can lead my work up down the wrong path. And if it’s a test I’m ordering, that has a dollar value attached to it.
JOHN: Hey, all good points. And all the more reason to ask: How do we get better at this? How do we master the game of Medical Twenty Questions? Well, on this episode, we’re going to explore this side of diagnostic reasoning. As usual, we’ve got an interesting, challenging case for you to try and solve — but, instead of giving you all the case data, like we’ve done in every episode up until this point, we’re going to present you with the beginning of a case, then ask you to think about what information you’d want next and in what order. And afterward, we’ll listen as our discussant for this episode tackles the case the same way.

With CoreIM, welcome to Hoofbeats. I’m John Hwang…

CINDY: …And I’m Cindy Fang…
JOHN: …And stay with us for the case.
JOHN: A 45 year-old woman is admitted to the hospital because of persistent bleeding from a surgical incision site on her left lower eyelid. Five days earlier, she had undergone elective excision of a chalazion that went uneventfully. (In case you’ve forgotten what a chalazion is, it’s a nodule of granulomatous inflammation usually left over after a bacterial infection of a Meiboian gland.) Two days after the procedure, she developed oozing from the incision site that persisted despite compression. She presented to an outside hospital’s emergency department, where bleeding continued despite two hours of continuous pressure. The bleeding was controlled with cauterization. Over the next two days she continued to experience intermittent oozing controlled with compression. The day of admission, however, she developed profuse intractable bleeding, prompting her to present to the ED. So that’s what we’ll start with. What else do you want to know?
CINDY: Keep in mind, we didn’t specify what order things had to be asked. You can ask for more history, a physical exam finding, a lab test, anything.
JOHN: Now, you can’t ask, but we can’t reach out to you directly. Though if you’re interested, let us know, maybe in the future we can make this interactive by having folks vote on social media. But for now, for this episode, we gathered up some of our CoreIM colleagues and recorded them taking this challenge together as a group. None of them knew the diagnosis. So we’ll reveal in stepwise fashion their questions and the answers, which I suspect will be representative of what most of you listeners want to hear.
CINDY: You’re on the honor system here. We’re trusting you to pause after each piece of information and think about what you’d ask next.
JOHN:On our crack team: Our fellow internists Amy Ou, Marty Fried, and Shreya Trivedi. Shreya unfortunately didn’t have her audio turned on. I’m not even going to comment on the irony of the chief executive producer of our podcast not turning on her sound.
CINDY: Joining them was Neil Shapiro, whom some of you might remember as the discussant from Hoofbeats episode 4. The one where we tortured you by choosing a case with an ambiguous final answer…
JOHN: Yeah… Neil still sounded bitter about that…
NEIL: C diff!! [Laughter]

CINDY: It was. It was C diff. We checked the stool.

NEIL: Thank you. I feel better! [Laughter]

JOHN: It’s not the diagnosis, but her stool was positive for C diff. [Laughter]

JOHN: So, once Neil got serious, the team started off by asking two questions about her history. First, they wanted to know, was she on anticoagulants or antiplatelet agents? The answer there was no — in fact, she was not taking any medications at all. Their second question was, was this her first lifetime episode of abnormal bleeding? And turns out, yes, aside from this current episode of bleeding, she had noticed that over the past year, she’s had unusually heavy menses — before, her flow never lasted more than a few days, but now she bleeds through multiple pads a day for more than a week at a time.
CINDY: Then the team jumped straight to the labs. They asked for a complete blood count, which showed that she was severely anemic to 6.5 with an MCV of 79. But her white cell count, differential, and her platelet count were all normal.
JOHN: For question four, they asked to see her PT/INR and PTT. These were both normal. (I guess I should’ve charged them for two questions instead of just one. Oh well.)
CINDY: Next, the team asked whether factor levels had been sent. And, yes, they were all normal — II, VI, VII, VIII, IX, and X.
MARTY: So if platelets aren’t going to explain the bleeding, and the coagulation cascade is normal, are there other things like von Willebrand’s factor, or any other…. Oh gosh… [laughter]

NEIL: You haven’t given us the renal function. Is it possible she has uremic dysfunction of her platelets?

JOHN: Her BUN and creatinine are normal.

NEIL: Darn. [Laughter]

CINDY: …Okay, so she’s not uremic, that’s question 6.
JOHN: And we also heard Marty there asking about von Willebrand disease. When I asked him what specific tests he wanted, I heard a long groan over Skype, followed by some keyboard clicking. (Full disclosure: I would have done the same.) To save you folks the trouble: Recall that there are different types of vWF disease; in some, the level of vWF is low, while in others, the vWF level is fine, but the factor itself is dysfunctional. So the tests you’ll want to order for vWF are the vWF antigen level, the vWF activity, and a factor VIII activity (since vWF is supposed to bind to and protect factor VIII from degradation). All of these were normal in this patient.
CINDY: The team asked for a peripheral smear. This came back pretty much what you’d expect — microcytic, hypochromic red cells of varying sizes, but no schistocytes or other abnormal RBCs. The white cells looks normal.
JOHN: At this point in the challenge, with all the tests coming back basically normal, the team drifts back to the patient’s history. For question nine, they asked whether she was eating anything unusual (like herbals). The answer: No.
CINDY: For question ten, they asked whether there was a family history of abnormal bleeding. The answer again, No.
JOHN: The team asked for her surgical history. She had a C-section 11 years earlier, when she was 34 and at eight months’ gestation, because of a non-reassuring fetal heart rate; this went uneventfully. Five years ago, her second child came out by elective C-section, again without any problems.
CINDY: They asked whether she had a history of miscarriages. But no, none. She just had those two healthy pregnancies.
JOHN: So that’s twelve questions down… And Marty pretty much summarizes how everyone on the team is feeling about the case so far.
MARTY: “So…. In transparency, here, I am just going through the UpToDate section on bleeding disorders right now. [Laughter]
JOHN: Finally, with test results unrevealing, history seemingly exhausted, the team turns to their last resort: The physical exam. (Our physician ancestors are rolling in their graves.) Specifically they ask whether there are any rashes, hemarthroses, or other skin abnormalities visible. Answer: None, nor does she recall having had any.
CINDY: They asked whether she had any neurologic signs on exam — weakness, paresthesias, and so on. But no, none of these were present.
JOHN: We’re up to our fifteenth question! The team asks whether there is anything abnormal on exam. Not sure if that’s cheating or not. But indeed, there is a finding: She has palpable non-tender hepatomegaly 3cm below the costal margin.
CINDY: Obviously then, they ask for a hepatic panel. The results? The transaminase levels are normal, at 37/20. But the alkaline phosphatase is markedly elevated, at 782. The total bilirubin over direct bilirubin is 1.8 over 1.2. The total protein and albumin are normal, 6.8 over 4.0.
JOHN: They follow that up with a GGT, which comes back significantly elevated to four times the upper limit of normal.
CINDY: They asked for an abdominal CT. That shows an enlarged liver, 22 cm in sagittal dimension. It looks smooth and homogenous, without masses. The vasculature is patent, and the bile ducts look normal. There’s no lymphadenopathy.
JOHN: Marty asked whether a bone marrow biopsy was performed, and whether it showed myelodysplasia. I can confirm that a bone marrow biopsy was performed, but it did not show myelodysplasia.
CINDY: And that’s it! That’s twenty questions.
JOHN: Not going to mince words: The team is confused. Neil is the first to sum up his thoughts.
NEIL: “This is where I’m struggling with this… The platelets are normal, the coags are normal, not on any medications or uremia to make the platelets not functional… All the markers that we have of bleeding disorders are not there. What you have is the liver being big. But if the coags, the PT being normal… something like primary biliary cirrhosis or autoimmune hepatitis giving you an elevated alk phos… That doesn’t really explain things for me. So that’s why I think I’m being quiet.”
JOHN: So, what do you think? Did you get the diagnosis ten questions ago and are now listening smugly?
CINDY: Was there a question you were screaming at them to ask that they didn’t?
JOHN: Well, finalize your thoughts, because after the break, we’ll hear how our expert discussant asked his questions, and how he solved this case.
JOHN: So, for this episode, we sat down with Dr. Lloyd Wasserman, a general internist and NYU faculty here at Bellevue Hospital. Remember, he’s starting at the very beginning with just that initial case stem we gave you — he doesn’t know anything about what the CoreIM team asked about — the anemia, the normal platelets, the normal coags, the surgical history, the alk phos, the hepatomegaly, none of that.
WASSERMAN: “Tell me if I remember correctly, she was a 45 year old woman who had a persistent chalazion in a lower lid when, uh, had, uh, uh, an excision or a debridement or whatever they did. And then she had delayed bleeding and it kept happening.”
JOHN: So Wasserman started off the same way our team did. First, he asked whether the patient was on any medications that would affect bleeding — recall that, no, she was not. Then, he explored her bleeding history.
WASSERMAN: So did she ever had menorrhagia or metrorrhagia before this?

JOHN: Before this, the start of this year, of this illness? No.

WASSERMAN: Okay. Other bleeding things I’d want. Did she ever have any other bleeding? Protracted bleeding after other minor procedures, like dental procedures?

JOHN: She doesn’t really get routine dental care. She couldn’t think of any minor procedures she had done.

WASSERMAN: Okay. Um, does she bleed a lot when she flosses? Or does she floss? Like most of us, or many of us?

JOHN: It’s a great question. I don’t think this was answered.

WASSERMAN: Okay. Or when she brushes her teeth even. Okay. And anytime, uh, bleeding when she has a bowel movement?

JOHN: None.

WASSERMAN: Uh, bruising, things like that?

JOHN: No bruising historically or recently.

WASSERMAN: Okay. So, you know, um, it makes a congenital problem that causes bleeding on, you know, they’re rare. Uh, it would probably be one of the first things they’d say to me if, if they came in with bleeding, but it makes a, a late diagnosis of a congenital disorder, less likely.

JOHN: In a game of Twenty Questions, mathematically speaking, the ideal strategy is to try to remove half of the possibilities with each question. Like, if I’m thinking of an integer between one and a million, and you’re trying to guess what it is, you’re not going to ask me, “Is it 7?” You’d be better off by asking, “Is the number less than 500,000?” or “Is the number even?” Cut the number of possibilities in half twenty times in a row, and you could theoretically distinguish between 2^20th, or over a million possibilities! There are only 70,000 diagnoses in the ICD10 total — and let’s be honest, we’re never going to see most of these. (Did you know W55.41 is ICD10 for “Bitten by Pig?” There’s even one for “Bitten by Pig, Initial Encounter.” W55.41XA. What does that even mean!?)

Expert clinicians understand which lines of questioning will enable them to most rapidly and efficiently narrow their problem space. We just heard Wasserman ask six questions in rapid succession, but they were essentially all different ways of getting at one deeper, and crucial, question: Is this patient’s bleeding disorder a congenital problem or an acquired one? By concluding it’s an acquired disorder, he’s bisected his problem space.

He next tries to cut that space by narrowing down which component of the hemostatic system is malfunctioning in this patient.

WASSERMAN: So when someone has abnormal bleeding, I think there are a few categories, right? So one is a dysfunction of platelets, which tends to be, uh, tends to occur at a time of trauma. If it’s trauma related, it’s not going to be later and then recurrent. And the platelet defects can be quantitative or qualitative, like storage defects, von Willebrands disease, et cetera. [Switched] Then there are coagulopathies, uh, which can be at the time of trauma or occur later and be coming and going. And those are basically disorders of hemostasis.
JOHN: Acquired versus congenital, medication-related versus unrelated, and now platelets versus coagulation cascade. What we see emerging here is Dr. Wasserman’s diagnostic schema for abnormal bleeding, though he himself doesn’t use that term explicitly.

We’ve talked about diagnostic schemata in prior episodes without really defining what they are. Chances are that you already use them, even if you’re not familiar with the term. For example, do you think about acute kidney injury in terms of pre-renal, intrinsic-renal, and post-renal causes? Do you divide causes of hypercalcemia into PTH-mediated versus PTH-independent processes? Those are schemata. They’re mental frameworks a clinician uses to organize their knowledge about a defined problem.

Almost everyone inherits from medical training a collection of somewhat generic schemata for basic problems like AKI and hypercalcemia. But with experience, awareness of context, and deeper understanding of pathophysiology, the schemata of an expert clinician can become highly personalized, and consequently much more powerful.

WASSERMAN: Let me step back and say, I should not immediately assume this is due from a disorder of platelet function or coagulation.
WASSERMAN: You can also have a soft tissue disorders, right? Although scurvy doesn’t usually present with, with conjunctival bleeding after chalazion, they can get postoperative bleeding because they don’t make hydroxyproline and they have soft tissue and vascular abnormalities associated with that and they tend to get problems lower down — they can have GI bleeding, gum bleeding. Other soft tissue vascular abnormalities that are not due to the coagulation or platelet systems that can be associated with bruising or bleeding… vasculitis, obviously; we diagnose it by finding palpable purpura.

And amyloid is one, right? So she’s, she’s young. That we know of, she doesn’t have a chronic inflammatory disorder. She’s not so young that it’s, it’s impossible for her to have AL amyloid.

WASSERMAN: If she has some other vascular lesion, like could, you know, could this chalazion uh, uh, be a vascular tumor that was mistaken for a chalazion, and then it would be interesting to see if they sent it for pathology. Okay. And what did it show?

JOHN: We’ll get there [laughter].

JOHN: Earlier we heard the members of our team divide the causes of abnormal bleeding into quantitative versus qualitative platelet disorders and coagulopathies caused by factor deficiencies or inhibitors. But we see here Dr. Wasserman’s schema includes a third group, vascular and soft tissue disorders, something that was never brought up by our team. And this leads to our discussant’s first and most significant deviation from what our team did: He asks for the pathology report of the excised chalazion. And believe it or not, this was one of the definitive diagnostic tests that led to the final answer.
CINDY: Just to be clear, this was five minutes into the interview.
JOHN: Right, and he had asked two questions, or two lines of questioning — medications and bleeding history. So me laughing at the end there, that was a mixture of surprise and slight panic.
CINDY: What do we do?! He figured it out too early!
JOHN: In the interests of continuing the exercise, we simply told him the pathology report wasn’t immediately available, and to continue thinking aloud. Same goes for you folks.
CINDY: That wasn’t a lie, in real life the path report did take time.
JOHN: His next set of questions was actually focused on making sure the patient is actually OK. He wanted to know about the vital signs, orthostatics, the hemoglobin. After that, he starts exploring the other categories in his schema. He asks for the platelet count, and the complete hemogram; as you recall, she was severely anemic, while her platelet count was normal.
WASSERMAN: And again, it doesn’t really sound to me like a platelet disorder because it’s late and recurring, although menorrhagia, or metromenorragia I think is typical of, of von Willebrand’s disease.
WASSERMAN: Since it’s late and recurrent bleeding, that makes me think more of a bleeding disorder or a local soft tissue disorder. Instead of looking down the von Willebrand syndrome pathway — again, if she did have a pathology I would call. [chuckles] I would look there to see is there something else there, right, that’s left behind? But if I can’t do that, then I think I’m going to start doing coagulation assays too.
JOHN: Just to point out: This is the second time he’s emphasized the delayed onset and recurrent nature of the patient’s bleeding. It’s a critical clue that the problem lies not in the formation of the platelet plug (i.e. primary hemostasis) — that would cause immediate bleeding. Again, he’s already suspicious for a soft tissue disorder, but with the pathology report pending, he plays along and starts to order coagulation studies.
WASSERMAN: So there are some simple tests in our armamentarium that can be helpful, right? In terms of thinking about bleeding. Um, if I’m, if I want to do my deductive method and we have our, uh, prothrombin time and our partial thromboplastin time respectively, both of them can be helpful in thinking about the common final pathway of the coagulation cascade and the prothrombin time for the extrinsic VII, factor VII, VIIa, and, and the PTT for the intrinsic, which I think are VIII, IX, XI, or VIII, IX, XI, XII plus the common pathway. So what is her PT/PTT?

JOHN: Her PT is 12.9, which in this laboratory is normal. Her PTT is 23.9 and again, in that laboratory, it’s normal.

WASSERMAN: So these being normal, it doesn’t totally rule out a coagulation disorder, but it makes it less likely that it is something to do with the extrinsic or the intrinsic pathway. It could be factor I or factor II. If it was a vitamin K deficiency, although that can affect factor II, it should also affect factor VII, IX and X. Vitamin K deficiency doesn’t generally occur with just malnourishment — they are usually on antibiotics. But speaking of which, is her diet OK?

JOHN: The way he explicitly talked about the factors here struck me. He could’ve just asked for the PT and PTT. Instead, he runs through the factors that contribute to each, before asking for the results.
CINDY: Is that surprising? I mean, that’s the way it’s taught in medical school.
JOHN: I’m not saying it’s arcane knowledge. I mean, yes, I also remember the factors from med school too, albeit with some effort. (I think.)
CINDY: [Laughter] I don’t!
JOHN: [Laughter] I’m sure you could recall them with some effort. But to be honest, somewhere in the ten years between when I learned the coagulation cascade and today, my brain decided to stop caring about which factors were part of what pathway. In the real world, as a general internist, being able to see an isolated PT prolongation and recognize, OK, that suggests an extrinsic pathway problem — I’ve got to think about warfarin, vitamin K deficiency, liver disease — most of the time, that abridged model of the pathophysiology is good enough in daily practice.
CINDY: You’re saying it’s almost like there’s a level of pathophysiology that’s not worth remembering. Once I enter the clinical world, certain things just don’t apply in real life anymore.
JOHN: I mean, don’t tell my medical students I said that, but… Yeah, kind of. I feel like pathophysiology is like an ocean — I can dive deeper and deeper, but beyond a certain depth, it’s just too dark and uncertain, and cold and sterile, and I drown. So that’s why I was surprised he’s got the factors in his working memory, he retrieves those details with such ease. And there’s a part of me that wondered, why does he bother to remember that? Should we bother to remember that? Isn’t it distracting?
JOHN: This became a recurring theme during our interview — Wasserman would get very granular in his discussion of pathophysiology. And while we certainly entertained the possibility his “teaching mode” was engaged — he has a reputation within our group for prodigious knowledge — it honestly felt like more than that. It felt like these “asides” were in fact a part of his diagnostic process.
WASSERMAN: It wouldn’t be, it’s less likely to be, I think type I Willebrand’s where you get factor VIII depletion. But acquired von Willebrand’s disease whether it’s from a high flow state or like aortic paravalvular leak or myelodysplastic syndrome, they often will have a normal von Willebrand factor level, a normal ristocetin test. And I don’t really remember exactly the details of that. And they will have a normal factor VIII and PTT, but they’re losing their large von Willebrand factor multimers that are the most important ones in terms of clotting. And that’s something I would think about. So did she get an evaluation for that?
JOHN: Just to remind you, both the quantitative and qualitative von Willebrand factor assays were normal, as was the factor VIII activity.
WASSERMAN: Okay. So it makes it less likely, but it’s not sensitive at all for certain conditions. And the problem is that the diagnosis is made by this von Willebrand multimer assay that is usually not done in most hospitals and is operator-dependent. But if I’m thinking she has acquired von Willebrand’s disease, I want a good reason why, right? So I’m still looking. I’m going to say that’s less likely, but I’m going to look for something that would cause that.
JOHN: So by this point, Wasserman is skeptical of platelet disorders and von Willebrand disease, and the coagulopathies bucket is shrinking quickly too.
WASSERMAN: So I think it’s unlikely she has a congenital deficiency of clotting factors. She could have an acquired inhibitor, which again, often you’re talking about secondary to another disease. So did she have a mixing study? Now she has a normal PTT. So usually you’re going to be doing those in someone with an abnormal PTT. So in terms of bleeding disorders, we’re talking about like a dysfibrinogenemia, which is very rare. Uh, it doesn’t look like she has DIC. Checking for a low fibrinogen or increased the dimers — did they do those?

JOHN: The fibrinogen level was 264, which is normal. I don’t think there was a D-dimer that was sent.

WASSERMAN: Okay. So I don’t, uh, so, you know, I, I don’t know that I would go checking for levels of coagulation factors. You can have acquired factor eight deficiency from von Willebrand’s disease. There may be other acquired deficiencies I can think of that are not related to an inhibitor, an antibody, uh, that I don’t know about. Are there, do you know? So again, I’m just going to say I want to know what was in the eye.

JOHN: If you’re keeping count, this is now the third time he’s asked for the pathology report, and it’s pretty clear he believes the answer is there. So before we reveal the biopsy finding, we ask what’s he’s looking for on the biopsy, what his leading diagnosis is.
JOHN: What would you… I’m curious…?

WASSERMAN: …Amyloidosis, amyloidosis. So does she have any reason to have AA amyloid? Does she have a chronic disease that, uh, associated with it? It’s extremely unlikely she has familial Mediterranean fever. Does she have, does she have some other chronic inflammatory disease and does she have other skin abnormalities?

JOHN: Okay, that’s fair. I’m not sure if you would ask her if you have any chronic inflammatory disease. But she doesn’t, for what it’s worth, no, she doesn’t. She was quite healthy until recently. A skin exam. No, normal. No hemarthroses, you know, rashes.

WASSERMAN: You can get localized cutaneous amyloid, and nodular can be systemic or cutaneous. Does she have any history or finding suggestive of other things you’d seen systemic amyloid? So, in myeloma and/or amyloid, does she have bone pain or evidence of bone injury with a high alk phos?

JOHN: Well, a couple of things that she doesn’t have bony pain per se. Evidence of bone injury in the form of a high alk phos? Her alkaline phosphatase was 782 on admission.

WASSERMAN: Wow. And do we have a GGT or a bony isozyme?

JOHN: We have a GGT, not an isozyme. The GGT is 470, which is four times the upper limit of normal.

WASSERMAN: Is there evidence of hepatomegaly or right upper quadrant tenderness or a distended gallbladder?

JOHN: So right upper quadrant tenderness. Yes, there’s tenderness in the right upper quadrant and a palpable liver edge three centimeters below the costal margin.

WASSERMAN: And was there any hepatic imaging? Sonogram?

JOHN: Sonogram. Hm. She did have an abdominal ultrasound. It showed an enlarged liver 22 centimeters sagittally. The echogenicity was normal and the portal vein and IVC were patent; the bile ducts were also patent.

WASSERMAN: And the spleen?

JOHN: On the abdominal ultrasound? It looked like it was mildly enlarged. There’s no measurement.

WASSERMAN: Okay. So she has a large liver, mildly enlarged spleen. High alk phos. High bili, without obvious, without large biliary duct obstruction or dilation. Okay. So, you know, you can have… So things that would give you a high alk phos with a large liver… An infiltrative process. She could have a coagulopathy related to the liver, but I would expect the INR to be elevated. I don’t know, but I’m thinking could she have amyloid in the liver, right? It’s one of the places you’ve got amyloid. AL amyloid can get the liver, the heart, kidneys. I’m just thinking she doesn’t have an obvious coagulopathy and she has late bleeding postop. And when I’ve seen late bleeding, it’s been non-platelet related coagulopathy or something local. And usually there’s something local is obvious. Maybe this wasn’t a chalazion.

JOHN: The pathology was initially interpreted as showing a lipogranuloma, but Congo Red staining revealed birefringent deposits in a perivascular distribution, consistent with amyloid angiopathy.
CINDY: [Applause] And this would explain her bleeding. The perivascular amyloid deposits lead to blood vessel fragility. There are other ways in which amyloid causes abnormal bleeding. The amyloid fibrils can bind factors, for example, causing an acquired factor deficiency. But those mechanisms didn’t seem to be in play in this case.
WASSERMAN: What was there, I guess we should talk about blood tests for monoclonal gammopathies. Did she have any?

JOHN: What would you…

WASSERMAN: Light chains?

JOHN: Her serum free light chains, kappa is elevated to 544, which is 15 times the upper limit of normal. The lambda was normal. Obviously the ratio is abnormal.

WASSERMAN: So I think we probably have a diagnosis. Did they feel this was enough information to make a diagnosis or did hematology need to do a bone marrow biopsy?

CINDY: Remember that in order to make that diagnosis, of AL amyloidosis, four criteria have to be met. The first is proving there is amyloid deposition in tissues, on biopsy; the second is showing the amyloid is leading to an actual syndrome, like cardiomyopathy or nephrotic syndrome.
JOHN: Check, and check. In this case, we’ve heard of at least two: Amyloid-related abnormal bleeding, and possibly hepatic amyloidosis.
CINDY: Right. We also need to prove it’s AL amyloidosis. Recall there are dozens of proteins that can accumulate into amyloid deposits — transthyretin, amyloid beta-peptide, etc. — and the ensuing clinical syndromes and treatments are completely different from one another. In AL amyloidosis, the amyloid deposits are fragments of light chains being produced by a plasma cell neoplasm. So you have to prove the amyloid is made of light chains, and you have to prove the existence of that plasma cell neoplasm.
JOHN: The markedly elevated lambda light chains in this patient are highly suggestive of both. And she ended up having a bone marrow biopsy that confirmed the presence of >10% clonal bone marrow cells. She did not have an M-protein. So the final diagnosis was in fact AL amyloidosis.
JOHN: So I was absolutely gobsmacked by Dr. Wasserman after this interview. It’s remarkable if you consider that he first brought up AL amyloidosis as a possibility within the first five minutes of the interview, after hearing the initial case and asking just two sets of questions.
CINDY: Not to mention that he heavily favored that diagnosis after just four more sets of questions (her clinical stability, her hemogram and differential with smear, the von Willebrands assays, and the PT/PTT.)
JOHN: Right. And that was without hearing her physical exam. That was before he knew of the LFT abnormalities — before there was really any indication, I think, we were dealing with a multisystem disorder. What accounts for his success?
CINDY: I’m curious to ask our listeners — if you got the diagnosis, great, tell us how you did it and brag at us on Twitter! — but if you didn’t get the diagnosis, why do you think that happened? When we asked this question to the CoreIM team after finishing the case, a couple of folks said it was a knowledge gap — they simply didn’t know that amyloid could present this way, with abnormal bleeding. But others actually knew amyloidosis could do this. Yet they were unable to recognize it in this case.
JOHN: And I think that brings up a key point: Knowledge alone is insufficient. Knowing that amyloidosis can cause abnormal bleeding is insufficient. The knowledge also has to be structured in a way that facilitates its retrieval during the diagnostic process. That framework, of course, is what we call a “diagnostic schema” — the very word skhema in Greek means “form,” or “shape,” or “figure”: Schemas give shape to our knowledge. We saw how Dr. Wasserman ran through his diagnostic schema for abnormal bleeding, which included, alongside platelet disorders and coagulopathies, that third category of reasons why people bleed, i.e. vascular and soft tissue problems — and it was in that context that his knowledge of amyloidosis was activated.
CINDY: So we’ve seen one clinician use his diagnostic schema to great effect in solving a challenging case. What is our take-home message here? I’m an attending; does this mean I should be focusing on teaching diagnostic schema on my rounds?
JOHN: That makes sense intuitively, but I feel it necessary to say that the research into this question isn’t conclusive. What we do know from studies published in the 1980s and 1990s is that expert clinicians are more likely to exhibit the use of schema in their diagnostic reasoning; students and non-experts tend to rely on more general, hypothetico-deductive methods of problem solving. But proving causality is difficult. Is it experts’ use of schema that causes them to be successful, or is their use of schema simply an epiphenomenon of their expertise? Will teaching students using diagnostic schema cause them to become more successful diagnosticians? These questions haven’t been definitively answered.
CINDY: And maybe that’s not surprising. I mean, how would you design those studies? Are you going to randomize students at your institution to receive standard versus schema-based instruction? And how forceful will the intervention be — are you merely exposing the students to schema, or somehow ensuring that they are used?
JOHN: Not to mention, in the cognitive science world, schema are specific to the individual who possesses them, shaped by their experiences and the context. A nephrologist’s schema for peripheral edema probably differs from that of an internist or a cardiologist, so whose schema gets taught?
CINDY: And if you are able to prove that instructing students with a schema for, say, metabolic alkalosis improves their ability to diagnose patients with this problem… how does that translate to other clinical problems, like chest pain, or chronic anemia?
JOHN: I don’t want to sound defeatist, like it’s impossible to study this in further detail. Several studies have in fact been published over the last two decades supporting the effectiveness of teaching diagnostic schema to students; these were largely written by faculty at the University of Calgary and McMasters’ University, who are thought leaders in this field.
CINDY: So if the N=1 ie. hearing Dr. Wasserman is not enough to convince all program directors to change the curriculum, back to my original question: what should be MY takeaway from this case?

Well, as a junior clinician, the conference going experience used to go like this: I would hear about a challenging case, the expert clinician who leads the conference would solve the case brilliantly like Dr. Wasserman did, sherlock style, and I would walk away excited and entertained,  thinking to myself “that was sooo cool! Next time I have a bleeding patient I got to remember to check amyloidosis. I’ll look so smart like him!

JOHN: You do, Cindy!
CINDY: Now that I did some growing up after residency, I realized that should not be my takeaway. That line of thinking only potentiates availability bias. Instead I should be asking myself: How do I incorporate the knowledge I’ve just learned from hearing this case into my existing schema? How can I optimize the way I organize that knowledge such that it will be correctly triggered when I encounter a similar case myself? And if I can’t easily incorporate this new knowledge, is my current schema for this problem even adequate — or is that a sign it needs to be completely reconstructed? Above all, am I thinking about the problem the way I should be?
CINDY: It’s worth noting that when we asked Dr. Wasserman if he himself was familiar with the actual term diagnostic schema, he just kind of looked at us blankly and said he didn’t know what that meant.
JOHN: [Laughter] Ditto for most clinical reasoning concepts. We got stares with “problem representation” and “illness script”.
CINDY: That’s true enlightenment. When wisdom is no longer effortful. When you can only see the Path and nothing else.
JOHN: For us disciples, though…. If we do accept that schema are something worth developing, how do we go about doing that? Well, we asked Wasserman, how did he develop his schema for bleeding? How did it come to include that third category of disease?
WASSERMAN: I’m lucky that I knew that. I had to write a chapter about something to do with scurvy and reading about it, you know, came across this literature of, you know, well what is, I started thinking, well, what is petechiae, why do people get it? What is per, you know, why did they get purpura? And you really need to include, uh, vasculopathy in that.
WASSERMAN: It’s nice when things make sense. They don’t always make sense. Often can seem like we’re just giving out a list of things that can cause something. And when you have these little, sometimes I feel like are the way we teach the pathophysiology is more important as a heuristic tool to help people remember things than as an understanding of how disease works. Because often we’re talking about things that we don’t even then the specialists in the field don’t understand. We’re talking about our own understanding but still heuristically it can be very helpful.

JOHN: So I think that’s really important idea. And you want to expound on that just a little bit more. Do you have an example of that? Um, cause I agree with you completely.

WASSERMAN: So for example, you know, I do a lot of consulting on psychiatry and… trying to remember which medications make people dizzy and pass out. We talk about alpha adrenergic antagonism in which ones are antagonistic in which ones are less so because it seems to correlate. Um, so I bring it up, it helps people remember. But the truth is it’s far from a linear correlation. It’s poorly understood. And these hypotensive effects are probably mediated by other things. But I bring it up because it helps the doctors taking care of the people, and whoever I’m teaching will remember that these agents can cause hypotension.

JOHN: Something that’s always bothered me about medicine is the unsettled truth that is pathophysiology, because with that comes the danger of being seduced by the beauty, rather than the truth, of an explanation. When a student asks you to explain why something happens — why this medication has this side effect, or how this organ malfunctioning lead to that symptom, or why this person who behaved a certain way develops an illness while others didn’t — how often do you use an explanation you’ve been taught or read or heard in passing, and liked — because it made sense — but that you yourself never verified? I acknowledge I do that more often than I want to admit.

That’s why I find it striking that Wasserman describes pathophysiologic explanations as a heuristic. Recall that the word, “heuristic”, refers to any problem solving method that is often practical or useful, without being perfect or optimal.

He’s acknowledging that our explanations are imperfect — incomplete, oversimplified, or in some cases, just wrong. And yet they’re indispensable in our work — and our growth as clinicians. Because it’s by trying to make sense of things, by asking why, that we look for new and better ways to think about problems. In other words, diagnostic schemata and pathophysiologic models are inseparable, as we witnessed while listening to Dr. Wasserman; strengthen one, and you strengthen the other.

CINDY: …So we’re not just learning this to sound smart…?
JOHN: …What the heck, Cindy….
CINDY: So how did the patient end up doing?
JOHN: Fortunately, she did well. She was started on CyBorD chemotherapy and is in remission. No more bleeding, no new organ problems, and no sign her underlying plasma cell disorder is developing into multiple myeloma.

Alright listeners, that should do it for this episode. As always, let us know what you think as our case formats continue to permutate.

 

References

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