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DIP Episode 80 - USMLE Step 1 Hematology Part 2

MixedMedium4 - HighHas Q&A

Step 1Step 2MedicineUSMLEStep 1Step 2

Topic

Coagulation disorders; Anemias (Iron, B12, Folate); Thrombotic microangiopathies; Bone marrow pathology; Hemostasis mechanisms.

Key Takeaway

Understanding the specific pathophysiology and management algorithms for common bleeding and clotting disorders, alongside differentiating the causes of various anemias, is crucial for high-yield board performance in hematology.

Runtime: 83.5 min

Published: 2019-02-15

Completed audio: Yes

Completed notes: Yes

Anki made: Yes

Section: HEME-ONC

Open Notion notes Episode source

Episode Notes

Source / episode info

Episode: 80
Title: Divine Intervention Episode 80 -USMLE Step 1 Hematology Part 2
Published: 2019-02-15
Source: Episode page

One-liner

Episode 80 provides a deep dive into advanced hematology, covering the nuances of primary vs secondary hemostasis (platelet disorders, vWF), differentiating megaloblastic anemias (B12/Folate deficiency), understanding thrombotic microangiopathies (TTP/HUS), and reviewing bone marrow pathology.

High-yield summary

Coagulation: Primary hemostasis involves platelets and vWF; secondary hemostasis relies on the intrinsic/extrinsic pathways, requiring factors like Factor VIII, IX, XI, XII, etc.
Anemia Differentiation: Iron deficiency is characterized by microcytic, hypochromic anemia with low ferritin; B12 deficiency causes megaloblastic changes due to impaired DNA synthesis and requires parenteral replacement.
Thrombotic Microangiopathies (TMA): TTP presents with the classic pentad (thrombocytopenia, microangiopathic hemolytic anemia [MAHA], renal failure, neurological symptoms, fever) and is often associated with ADAMTS13 deficiency; HUS typically follows nephritides/GI bleeding.
Bone Marrow: Pancytopenia suggests marrow failure or infiltration; the differential diagnosis must consider nutritional deficiencies (B12/Folate), aplastic anemia, or malignancy.
Bleeding Workup: A prolonged PT points to extrinsic pathway issues (Warfarin); a prolonged aPTT points to intrinsic pathway issues (Heparin/Factor deficiency).

Learning objectives

Differentiate between primary hemostasis defects (platelet count vs function) and secondary hemostasis defects (factor deficiencies).
Correctly diagnose the cause of megaloblastic anemia (B12 vs Folate deficiency) and determine appropriate replacement therapy routes.
Apply knowledge of thrombotic microangiopathies, distinguishing TTP from HUS based on clinical presentation and ADAMTS13 levels.
Understand the mechanism and management implications of common bleeding disorders like hemophilia or vWD.
Interpret bone marrow findings (e.g., dysplasia, fibrosis) to narrow the differential diagnosis between aplastic anemia and myelodysplastic syndromes.

Board exam buzzwords

Condition	Key Finding	Association	Board Exam Tip
TTP	Thrombocytopenia + MAHA + Renal failure + Neuro symptoms	ADAMTS13 deficiency (inhibitor)	Always think of the pentad when presented with TMA; low ADAMTS13 is key.
B12 Deficiency	Megaloblastic anemia, Glossitis, Subacute combined degeneration	Parenteral administration required	If the question implies neurological involvement, suspect B12 over Folate deficiency.
HUS	Thrombocytopenia + MAHA + AKI	Shiga toxin-producing E. coli (STEC)	GI bleeding preceding renal failure strongly suggests STEC/HUS.
Warfarin Therapy	INR prolongation	Vitamin K antagonism	Remember that the PT is the test most sensitive to warfarin's effect on the extrinsic pathway factors.

Rapid review table

Topic	Key Point	Context	Exam Relevance
TMA	TTP: ADAMTS13 deficiency; HUS: STEC toxin	Both cause thrombocytopenia and MAHA, but etiology differs significantly.	High-yield differential diagnosis question setup.
B12 Deficiency	Requires parenteral (IM/IV) replacement	Impaired DNA synthesis leading to large, immature RB Cs (megaloblasts).	Distinguishing B12 from Folate deficiency is a common trap.
Coagulation Cascade	PT measures extrinsic pathway; aPTT measures intrinsic pathway	Warfarin affects factors II, VII, IX, X (measured by PT); Heparin primarily affects the intrinsic pathway (aPTT).	Essential for interpreting coagulation panels in clinical practice.
Bone Marrow Failure	Pancytopenia + Dysplasia/Fibrosis	Aplastic anemia vs MDS requires careful assessment of marrow cellularity and morphology.	Helps distinguish primary failure from malignant infiltration.

Board-speak -> diagnosis

Board-speak / Vignette phrase	Diagnosis / Concept	Why it fits
A patient presents with thrombocytopenia, MAHA, acute kidney injury, and neurological symptoms. ADAMTS13 levels are low.	Thrombotic Thrombocytopenic Purpura (TTP)	The combination of the pentad and the specific deficiency in the large vWF cleaving enzyme is pathognomonic for TTP.
A patient with chronic diarrhea develops macrocytic anemia, glossitis, and neurological deficits.	Vitamin B12 Deficiency	B12 deficiency causes impaired DNA synthesis (megaloblastic changes) and affects peripheral nerves (subacute combined degeneration).
A patient on warfarin presents with a bleeding diathesis; PT is prolonged, but aPTT is normal.	Warfarin Overdose/Vitamin K Antagonist Effect	Warfarin primarily inhibits Vitamin K-dependent factors (II, VII, IX, X), which are measured by the PT.
A young child develops acute kidney injury and thrombocytopenia following a diarrheal illness with bloody stools.	Hemolytic Uremic Syndrome (HUS)	HUS is classically associated with Shiga toxin-producing E. coli (STEC) infection, leading to platelet consumption and microangiopathic hemolysis.
A patient presents with pancytopenia and elevated reticulin fibrosis on bone marrow biopsy.	Myelodysplastic Syndromes (MDS) or Aplastic Anemia	Pancytopenia suggests failure of the hematopoietic stem cell niche; MDS involves ineffective hematopoiesis leading to dysplasia.
A patient has a history of GI bleeding and develops progressive, osteoblastic bone metastases.	Prostate Cancer Metastases	Prostate cancer classically metastasizes via the bloodstream to bone in an osteoblastic (sclerotic) pattern due to high levels of PSA/androgens stimulating osteoblasts.

Differential diagnosis / distinguishing features

Megaloblastic Anemias

Key Features	Distinguishing Findings	Next Step
B12 Deficiency	Neurological symptoms (peripheral neuropathy, subacute combined degeneration); Glossitis	Cobalamin injections (Parenteral).
Folate Deficiency	Macrocytic anemia; Glossitis; No prominent neurological deficits	Oral supplementation (Dietary/Oral).

Bone Marrow Failure Syndromes

Key Features	Distinguishing Findings	Next Step
Aplastic Anemia	Pancytopenia, hypocellular marrow, no dysplasia	Immunosuppressive therapy (e.g., ATG + Cyclosporine).
Myelodysplastic Syndrome (MDS)	Dysplasia in one or more lineages; Hypercellular/hypocellular variable	Risk stratification and potential for supportive care or transplant evaluation.

Management pearls

TTP Treatment: Immediate plasma exchange (PLEX) is the cornerstone of therapy to replace deficient ADAMTS13 activity.
Warfarin Reversal: Vitamin K antagonists are reversed with high-dose Vitamin K, followed by PCC (Prothrombin Complex Concentrate) if rapid reversal is needed for major bleeding.
B12 Deficiency Management: Because B12 deficiency can cause irreversible neurological damage, treatment must be initiated promptly and often requires IM/IV administration regardless of initial serum levels.
Iron Overload: Iron chelation therapy (e.g., deferoxamine) is used to bind excess iron, particularly in conditions like thalassemia or chronic hemodialysis.

Don't miss

🚨

Never assume a patient with thrombocytopenia has ITP; always rule out TTP/HUS first by checking ADAMTS13 and reviewing the clinical picture.

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The difference between B12 (cobalamin) and Folate deficiency is critical: B12 deficiency carries a high risk of irreversible neurological damage.

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In bone marrow pathology, dysplasia suggests an underlying clonal process (MDS), whereas simple hypocellularity might suggest aplasia.

🚨

When managing anticoagulation, always consider the patient's baseline renal function, as many factors are cleared renally.

Integration & clinical reasoning

Hematology & Nephrology: TMA is a critical overlap area; recognizing the difference between STEC-HUS and TTP is vital for appropriate management (antibiotics vs PLEX).
Endocrinology & Hematology: Vitamin B12 deficiency can sometimes mimic or coexist with adrenal insufficiency, requiring comprehensive endocrine workup.
Oncology & Hematology: Understanding bone metastases patterns (osteoblastic vs lytic) helps predict the underlying malignancy and guide imaging/biopsy interpretation.

OMM / COMLEX integration

🦴

For COMLEX: know these viscerosomatics / Chapman points, but don't let OMM distract from emergent diagnosis and management.

Viscerosomatics: While not directly emphasized, understanding the systemic nature of TMA (affecting kidneys and brain) relates to visceral organ dysfunction impacting distant systems.
OMM/OMT Contraindications: In any acute, unstable patient presenting with severe bleeding or coagulopathy, the primary focus is immediate stabilization and reversal agents (Vitamin K, PCC), overriding elective OMM procedures.

Concept connections / cross-references

For detailed information on renal physiology and AKI causes: Divine Intervention Episode 37 .
For general principles of endocrine disorders, including adrenal insufficiency: Divine Intervention Episode 12 .
For understanding GI bleeding sources and workup: Divine Intervention Episode 45 .

High-yield association table

Condition	Association	Mechanism	Clinical Significance
TTP	ADAMTS13 deficiency	Deficiency in the enzyme that cleaves large vWF multimers, leading to uncontrolled platelet aggregation.	Requires urgent plasma exchange; life-threatening if untreated.
HUS	Shiga toxin (E. coli)	Toxin damages endothelial cells lining small vessels (microangiopathy).	Classic triad: Diarrhea -> Thrombocytopenia -> AKI.
B12 Deficiency	Impaired DNA synthesis; Methylmalonic acid buildup	B12 is a cofactor for methylmalonyl-CoA mutase, leading to accumulation of toxic metabolites.	Must be treated parenterally due to potential irreversible neuropathy.
Prostate Cancer Mets	Osteoblastic/Sclerotic pattern	Prostate cancer secretes factors that stimulate osteoblasts more than osteoclasts.	Helps differentiate from other bone metastases (e.g., lung = osteoblastic/sclerotic).

Key terms glossary

Term	Definition	Context	Example
MAHA	Microangiopathic Hemolytic Anemia	RB Cs are sheared/fragmented as they pass through partially obstructed, damaged small vessels.	Seen in TTP, HUS, and DIC; characterized by schistocytes on smear.
Megalo-blast	Large, immature cell with nuclear-cytoplasmic asynchrony	Found in B12 or Folate deficiency due to impaired DNA synthesis relative to protein synthesis.	A peripheral blood smear showing large RB Cs/lymphocytes is highly suggestive.
PT (Prothrombin Time)	Measures the extrinsic coagulation pathway (Factors VII, X, V, II, I)	Used clinically to monitor Warfarin therapy; prolonged by Vitamin K antagonists.	If PT is abnormal but aPTT is normal, suspect warfarin effect.
ADAMTS13	A metalloproteinase enzyme that cleaves large von Willebrand factor multimers.	Deficiency leads to uncontrolled platelet aggregation and microthrombi formation.	Low levels are diagnostic for TTP.

Study optimization

Topic	Study Approach	Priority	Resources
TMA Differentiation	Create a flow chart: GI Bleed -> HUS; Systemic/Neuro -> TTP.	High	Review board questions focusing on the pentad and ADAMTS13 levels.
Anemia Workup	Use elimination logic: Microcytic (Iron) vs Macrocytic (B12/Folate).	Medium-High	Memorize the specific treatment modality for B12 vs Folate deficiency.
Coagulation Testing	Understand which pathway is tested by PT vs aPTT and what drugs affect them.	High	Practice interpreting coagulation panels in vignettes involving anticoagulants.

Question pattern recognition

The "Best Fit" Diagnosis Pattern: Given a constellation of symptoms (e.g., thrombocytopenia + MAHA + AKI), the student must select the most specific diagnosis (TTP vs HUS).
Management Algorithm Pattern: Determining the next step in management based on initial lab results (e.g., prolonged PT -> Vitamin K/PCC; prolonged aPTT -> PCC/FFP).
Deficiency Differentiation Pattern: Distinguishing between similar-sounding deficiencies (B12 vs Folate) by linking the deficiency to its unique clinical hallmark (neurology for B12).

Test yourself

Common mistakes to avoid

🚫

Confusing the mechanism of TTP (enzyme deficiency) with HUS (toxin damage).

🚫

Forgetting that B12 deficiency can cause neurological symptoms, making it more concerning than simple anemia.

🚫

Overlooking the specific factor deficiencies tested by PT vs aPTT when interpreting coagulation panels.

Common traps

⚠️

The "Normal ADAMTS13" Trap: Never assume TTP is ruled out if ADAMTS13 is normal; consider other causes of TMA like drug-induced or autoimmune vasculitis.

⚠️

The "Oral Supplementation" Trap: Assuming that because the anemia looks megaloblastic, oral supplementation (like folate) will fix it—it won't if B12 is deficient.

⚠️

The "Bleeding Source" Trap: Attributing bleeding solely to platelet count; remember that factor deficiencies or vWF issues can cause severe bleeding even with normal platelets.

Original transcript with highlights

Okay, welcome. My name is Divine. I am a PGY1 transitional year resident that's ultimately going to be going into radiology. And this will be the ADF episode of the Divine Intervention Podcasts. And really in today's episode I will be continuing my discussion of hematology and oncology. This is probably more hematology podcast. And yesterday I know I started talking about like the two cascades like the primary, the most easy secondary, the most easy talked about all of that. And then I integrated a lot of diseases along the way. So I'm going to sort of like use this podcast to like really hone in on those diseases. And make sure we talk about the high-year details for most of them. And then I also talk about a bunch of new diseases that basically kind of like involved pleatlets that I did not necessarily mention yesterday. And then in the next podcast to begin to go into like the red blood cell stuff, the white blood cell stuff, the cancer stuff and sort of go from there. But again, like I said, under the video, I mean, under the podcast yesterday, there's already podcast for him from ecology at onc from ecology, right? So I need to cover those again. If you just sort of go down in the website, you'll find them in one of the older episodes. Okay. So, I guess let me sort of again, same format as yesterday. I'll start with a key. So let's assume you get a question about a patient that is... You know, 50 years old, right? And this person has some kind of hematologic malignancy.

Okay. So let's say, you know, in the process of training that hematologic malignancy through, I don't know, let's say we are doing like some kind of surgical procedure or biopsy or something. The person, you know, kind of becomes unresponsive. And you check there, you check, you know, you check some basic labs. And you notice that the achymoglobin that was like 12 when they came into the hospital is now like eight or seven. And the applicable count is also like super low and all the achymatologic labs are kind of like all screwed up, right? So the PT is high. The PT is high. The bleeding time is high. The fibrenogen is low. They have schistocytes on blood, smell that stuff, right? If you see that, I really hope you're thinking about DIC, right? And hopefully you're thinking about the... You're thinking, I mean, you... That's the thing about step one, right? Again, these USMLE exams, yeah, don't get me wrong. I'm not gonna downplay the fact that they're tough, right? But it's all about just being able to put things together, right? So hematologic malignancy, DIC, I really hope you're thinking about... I could pro-mylocetic leukemia, right? So remember, I could pro-mylocetic leukemia. That's where you have the... The 15, 17 translocation, right? And remember that that's where you classically have the hour rods within your myeloid cells. And those hour rods, right? Say, for example, if they spill into the circulation, they can actually activate the coagulation cascade.

And if that happens, guess what? You're running to DIC, right? I mean, they're all that classically... So basically, if you sort of see my thought process with this, you can see how your friends at the MBME can construct many USMLE questions, right? So, for example, they can give you a question about a pregnant woman that delivers a baby or she has had like prolonged rupture of membranes. And then she delivers a baby and then becomes unresponsive, right? You're probably thinking about like a mniotic fluid embolism with that. Because remember, there are many constituents of a mniotic fluid that again can just sort of be released into the circulation and cause this massive activation of the coagulation cascade. And my other classic way you can test this is in a patient that has... That has like preeclamsia, right? So remember, again, preeclamsia, remember that spectrum, like preeclamsia, aclamsia, helps syndrome, all that stuff, right? And all those things can ultimately cause... You just... the milieu around the mniotic fluid can... At least some... let's put it this way, some contents of the mniotic fluid and some stuff in the uterus can again trigger the coagulation cascade and cause a lot of trouble, right? Another classic one that makes sure is a woman that they say, oh, like five days ago, her baby stopped moving, right? And she was like, that's kind of weird, and come to the hospital. And then sometime during that hospitalization, the lady becomes unresponsive, right?

The thing that happens is whenever you have like a dead fetus, right? That can again. That's why you don't... I mean, you can... if a lady, for example, has a dead fetus, right? The responsible thing she does in the physician is, you know, show your empathy and all that stuff. But one thing you need to remember is you cannot sit on it, right? You need to get that baby out as quickly as possible, because guess what? Those are constituents of the mniotic fluid and the uterus, again, can cause a massive activation of the coagulation cascade and you can run into the ICU very quickly in those patients. So, basically, right, this case that I just mentioned is basically... The reason for this certain of a DIC, so that diagnosis here is DIC, right? So, DIC, it's kind of like a weird condition. But basically, I'll say if you want to think about pathophysiology, almost always the thing that happens is you have some substance that's released into the circulation that can cause like a massive activation of the coagulation cascade, right? And as that happens, right, you begin to deplete your pleatlet, so you get a thrombocytopenia. As you begin to, you know, keep activating, activating, activating the coagulation cascade, you form all these like pleatlet thrombi in your blood vessels. So, as your blood cells sort of move through those blood vessels, those pleatlet thrombi sticks begin to share those red blood cells.

And if you think about it right, as you share those red blood cells, you have an anemia, right? So, your red blood cell count will go down, your hemoglobin will go down. Other things that will happen will be that because your red blood cells are exploding, right? The contents of red blood cells, right? So, like LDE, right? They'll begin to be spilled into the circulation. So, your lactate dehydrogen is will go up. Remember, LDE is heavily expressed in red blood cells, because remember, red blood cells don't have... They don't have mitochondria, right? So, they only do like anaerobic metabolism. Hopefully, that's something you remember from the bio-camer video. And then, right? Because you're constantly, constantly, constantly, turning over your pleatlets again, your pleatlet count goes down, your red blood cell count goes down, your LDH goes up, right? Because you're sharing your red blood cells, you see a lot of schistocytes on a blood smear, right? Other high yield things that may happen is, in the process of DIC, you also begin to activate plasmin a lot, right? So, all that plasmin can begin to chop up your fibrene. And remember, one of the breakdown products of fibrene, they're called like Fibrene Degradation Products. And a specific subset of them is your D-Dimer, right? So, your D-Dimer will be massively elevated in the setting of DIC, right? And if you think about it, right?

Again, DIC, I sort of think of it as a condition where you're making a ton of fibrene, but you're also breaking down a ton of fibrene, right? And remember, if you're making a ton of fibrene, fibrene is the activated form of fibrene origin. So, if you keep making, making, making fibrene, your forming cloth, your breaking down that cloth, it's like you're thrombosing your blood vessels, but you're also sort of bleeding out, because you also get, in that massive activation of your coagulation cascade, you're using up your platelets at an acillary-thed clip, right? So, that thrombocytopenia can predispose your bleeding, okay? So, because you're making all these cloths, right? Remember, if you want to make a strong platelet block, you need to convert Factor 1, which is fibrene origin, to Factor 1 A, which is fibrene, which is, and remember, that is all on that, the control of thrombin, right? Factor 2 A. So, if you keep using up your fibrene origin to make fibrene, you can already see that your fibrene origin levels should be low in the setting of DIC. So, that's kind of like all I'll say about a DIC, and I guess I'll go ahead and move on from that. So, again, I have like an outline of what I want to discuss, like just list of topics. So, you may see all these arms and ass again, I apologize. I'm just basically kind of making this from memory. Okay.

So, we talked about the, what Willy Brandt is easiest to do, we talked about the hemophilia, remember yesterday I said I'll talk about like the different, the differences between platelet bleeding and clotting factor bleeding. So, platelet bleeding, right? So, those people tend to have like very heavy men's teeth, right? So, one of the most classic presentations of Willy Brandt's disease on an exam is a lady that just has just really bad menorazia. Also, like nose bleeds, you know, or like skin findings like the TKI people, if you see those things, you want to think more about platelet problems, right? So, like, like, when Willy Brandt is these, where you have a deficiency of a Willy Brandt factor, or like a Bernat-Sulye disease, right? Where you have a deficiency of GP1 B, or what is this thing called? Glansman thrombostemia, right? Where you have a deficiency of GP2 B3 A, and then also remember ITP, immune thrombocytopenia, right? Where you have a deficiency. I mean, sorry, not deficiency, you make autoantibodies against the GP2 B3 A, okay? Those things are basically affecting platelets, so you should observe a platelet pattern of bleeding in those patients. Contrast our hemophilia as right where, classically, hemophilia on an exam may present as like a thritis, right? So, like those, can describe like a young person that has like osteoarthritic features, right? Because of just, they're just bleeding into their joints, right?

The bones, bones were for that on an exam, these are hematrosis, right? Or they tell you that all this person had like a procedure, like a dental procedure, and they had like a life-threatening bleeding afterwards that required like transfusion. And you really want to think about a clotting factor disorder, right? Because the thing is, in general, platelet disorders, they cause like, you know, like just kind of like small bleeds, right? So like micro-hemorrhages, but if you have a clotting factor disorder, you can have like big bleeds, right? Like micro-hemorrhages. You can get into trouble relatively, relatively quickly. And then, so that's how you sort of differentiate between the different kinds of the platelet bleeding where again you have more like an elevation in your bleeding time and your clotting factor bleeding, right? And remember, I mentioned yesterday that, I mean, we, I guess we can even run through this real quick, right? If a patient bleeds a lot, and their bleeding time is elevated, their histocity and co-factor assays abnormal, and their PTT is elevated, right? That should tell you that they have what? That will be from Williams disease. Again, I talked about the pathophys behind all that stuff in the podcast from yesterday. And then, what if a patient has an elevated PTT, okay? And it's a girl on tests. And the PTT is normal, the bleeding time is normal. What does that tell you? Good, that has to be hemophilia C, right? That's the factor 11 deficiency.

Remember, that's inherited in a non-rosomal recessive fashion. But what if a patient has an elevated PTT normal bleeding time? It's a boy, right? The PTT is fine, the bleeding time is fine. Hopefully, that tells you that that's hemophilia A or B, okay? Because remember, those are excellent recessive inheritance. So they are only common in boys, right? I mean, actually, on MBM, they should never happen in girls, only in boys, okay? And again, if they give you a question where it's non-descript, and you're like, yeah, this is a legit hemophilia. And they give you hemophilia A and B, both in the answer choices, code hemophilia A, because again, it's a lot more common than hemophilia B. And we talked about the treatment of hemophilia A, for example. I mean alternatively, you can also give, like, you know, basically, them back what they've lost, right? So like, recommend like factor 8 if for hemophilia A or factor 9 for hemophilia B or factor 11 for hemophilia C. And then also don't forget yesterday, I talked about where a patient may have like a hemophilia-like presentation, okay? But again, it's usually like a kid that's like less than two years old, but the PT is fine, the PT is fine, the bleeding time is fine. If you see that, you really want to think about a factor 13 deficiency. It doesn't have a specific name, it's just a factor 13 deficiency. There's one of those weird, bizarre things you want to keep at the back of your mind.

And then again, I explained the pathophysiology behind all of that yesterday. Really my purpose today is to try to bring all those disorders I discussed yesterday together. Yes, there was heavily focused on pathophysiology, but today I want to focus on making sure I sort of give you like the, again, just sort of remind you of the high yield salient points I discussed yesterday, and also talk about sort of like a bevy of a new, new diseases. So hopefully you understand those permutations I just discussed. I think that should make it a lot easier for because if you, those are basically the labs, right? Like, oh, this is high, this is low, and then they'll give you these weird scenarios. Many times if you sort of have the understanding based on what we discussed yesterday, you should be able to have no issues resolving these disorders in seconds on your exam. Now, let's assume you get a question, right, about a patient, right, that this guy, whenever he takes a shower, he begins to each a ton, right? And let's assume he's like a 60 year old guy, and then they tell you that, you know what? This guy had, this guy like, I don't know, like three weeks ago, he presented to the emergency room because he had like really bad red-o-pacadron pain. And when the physician in the ED saw him, he was like, man, you don't have any history of liver disease.

He was sort of looking through his shirt, he was like, man, you don't have any history of liver disease, but look at this powerful aside, he's that this person has. But when you examine the guy father, you did not observe any JVD, you did not hear any crackles in the lungs, it's just literally they just had like just really prominent aside teeth. And then let's say you're like, you know what, it's a good physician, let me go ahead and tap this aside, right? So you do a parcentises, and then you withdraw some of that acidic fluid, and you measure the gradients, the sag gradient, right? The serum, the albumin, what does the sag gradient mean? So the serum, the side is albuming gradient. I'm like, man, this is greater than 1.1. So that tells me that, okay, this is likely portal hypertension, that's the cause of this person's are, asides, right? But because if you think about it, asides usually is like chronic alcoholic, bloody, bloody, bloody, bloody works, right? But if you see a cute onset of side is an a patient that, for example, like this one that does not use alcohol, you hopefully sort of tie all this together like, oh, this person, old guy takes a shower, has a ton of each end, or old guy, I mean, if I give you this extra buzzword, everyone will get it right. This A has a rody complexion on physical exam. Hopefully this makes you think about polycythemia vera. Those are essentially the different ways they can present it to you on a test.

So polycythemia vera, basically, it's, you want to remember that it arises in the setting of a Jack 2 mutation, okay? A Jack 2 mutation. I remember polycythemia vera is one of the myeloproliferative disorders, just like CML. But I'll talk about those myeloproliferative disorders in more detail in one of the upcoming podcasts. But basically, polycythemia vera, you have a Jack 2 mutation, right? So you begin to make a crap ton of red blood cells, right?

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So that's why usually the patient has a heck so what if he's all that you give you don't give anti-bodies, but anti-bodies, actually make it worse. Okay. So let's talk about the pathophysiology behind all of this, right? And I think you'll make more sense to talk about the pathophys behind TTP first and then I'll talk about the pathophys behind H to S.

Although it's more like in fact these days, especially when you get into your third year, they just call it TTP H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and the H and th

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So one of the downstream events that happens is that you have a poptosis of endothelial cells. So you may say, okay, to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find a way to find The other thing that happens actually with that signaling cascade of the sheger like toxin binding to those GB3 receptors is that you also ultimately in activate atmcs 13 so in this case you're not making any autoantibodies against atmcs 13 as we have in TTP. What you're creating is you're literally just inactivating atmcs 13 and when you're inactivating atmcs 13 right again you have a willy-brown factor on your timers will not be chopped up anymore so you have massive activation of a primary hemostasis.

You found those so your platelet count will go down because you had the platin platelets and you found all those platelet from by sticks in your blood vessels if you have that happening right again you will share your red blood cells so you have a hemolytic anemia. So for those people I mean you may even see like if you do a blood smear you can see like schistocytes right and again they'll have high levels of indirect bilirubin they'll have low levels of haptoglobin already describe the mechanism behind all those things. And one concern I guess you may have is divine why is he to why is he to us more common in kids compared with adults here's the reason. The thing is those GB3 receptors that I said are bound by the shegun like toxin you actually find much greater numbers of GB3 receptors in kids in comparison with adults right so that sort of answers that question. Another question we have is okay divine this is kind of weird why does TTP he to us professionally affect the brain and the kidneys.

The thing is again it's all explained by these GB3 receptors these GB3 receptors are found predominantly or I mean they are found in many parts of the body but you'll get you find much larger populations of GB3 receptors in the kidneys especially like the glomerular capillaries remember your glomerular capillaries guess what they are lined by endothelial cells right so again those GB3 receptors if you have a poptosis of those endothelial cells lining those glomerular capillaries you can trigger. Primary he most this is because you're exposing all of that subendothelial collagen at the level of the glomerular capillaries right that's why the kidneys can be transiently sort of nuked in the setting of HUS right but you also find a large preponderance of those receptors in the central nervous system okay so that's why again you can get kidney injury and CNS injury in the setting of TTP HUS. So hopefully that sort of clears up a certain certain things for you because I always wonder like why why do you have all these you know just weird weird weird findings in the setting of HUS really if you sort of think through it sort of think through the pathophysiology pretty much all of it pretty much all of it makes make sense and really how do you how would you treat a TTP HUS.

I mean the indicator treatment is like you do something called like an exchange transfusion that's like the preferred treatment you can also do like plasma for SS I mean every so often you'll see them say oh you know what how about we give this person like steroids and IVIG those don't really work as well in general actually in fact I'll see IVIG is usually not given I mean you can give steroids but really you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of time and you can give them a lot of I want to talk about what if you get a question about like a lady and tell you that she has had how do I put this?

Tell you that she has had multiple miscarriages and then tell you that she has had p.e.s and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts

and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts a

nd dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts

and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dv

ts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and

dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dv

ts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and

dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts an

d dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d vts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dv and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvt

s and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d vts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dv and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts

and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvt

s and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d

vts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and

dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts a

nd dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts

and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dv

ts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts a

nd dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts

and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dv

ts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and

dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts an

d dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts

and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvt

s and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d

vts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and dvts and d

Practice questions — USMLE style

Question 1 — Hematology/Coagulation

A 32-year-old woman presents to the emergency department following a severe eclamptic seizure. On initial lab workup, she has a hemoglobin of 9.5 g/dL, a platelet count of $75 \times 10^9$/L, and an elevated prothrombin time (PT) and activated partial thromboplastin time (aPTT). Further testing reveals significantly low fibrinogen levels, schistocytes on the peripheral smear, and markedly elevated D-dimer. The physician suspects a consumptive coagulopathy. Which of the following is the most likely diagnosis?

A) Disseminated Intravascular Coagulation (DIC)
B) Thrombotic Microangiopathy (TMA) secondary to eclampsia
C) Vitamin K deficiency
D) Severe acute bleeding due to trauma
E) Hypofibrinogenemia

Answer: A. The constellation of findings—thrombocytopenia, prolonged PT/aPTT, hypofibrinogenemia, schistocytes, and elevated D-dimer—is classic for Disseminated Intravascular Coagulation (DIC). DIC is a consumptive coagulopathy triggered by massive activation of the coagulation cascade. In this specific clinical context (eclampsia), the underlying trigger is likely related to placental/amniotic fluid constituents causing widespread endothelial damage and subsequent clotting factor consumption.

Question 2 — Hematology/Thrombosis

A 45-year-old man presents with acute onset oliguria, confusion, and petechial rash. Laboratory studies reveal thrombocytopenia and evidence of microangiopathic hemolytic anemia (MAHA). Coagulation studies are normal, but the physician suspects a defect in fibrinolysis or platelet function due to his symptoms. Which enzyme deficiency is most likely responsible for this patient's condition?

A) Factor VIII
B) ADAMTS13
C) von Willebrand factor
D) Platelet glycoprotein I Ib/II Ia (GP2 B3 A)
E) Factor XIII

Answer: B. The clinical picture of thrombocytopenia, MAHA, and acute kidney injury strongly suggests Thrombotic Thrombocytopenic Purpura (TTP). TTP is caused by a deficiency in the metalloprotease ADAMTS13, which normally cleaves large von Willebrand factor multimers. Deficiency leads to uncontrolled platelet aggregation and widespread microthrombi formation, resulting in consumption of platelets and red blood cells. The primary treatment for TTP involves plasma exchange (plasmapheresis) to replace deficient ADAMTS13 activity.

Question 3 — Hematology/Coagulation Cascade

A young male patient presents with a history of deep joint bleeding episodes (hemarthrosis) following minor trauma, and his parents report similar issues. Coagulation testing reveals a normal platelet count and normal bleeding time, but an extended aPTT. The physician suspects a deficiency in a specific clotting factor. Which of the following factors is most likely deficient?

A) Platelet glycoprotein I Ib/II Ia (GP2 B3 A)
B) Factor XIII
C) Factor VIII
D) von Willebrand factor
E) ADAMTS13

Answer: C. The presentation of recurrent, spontaneous hemarthrosis and a prolonged aPTT with normal platelet count points strongly to a deficiency in an intrinsic clotting factor. Hemophilia A (Factor VIII deficiency) is the most common severe inherited bleeding disorder and classically presents this way. While Factor IX deficiency (Hemophilia B) also fits, Factor VIII deficiency is statistically more common and represents the classic board presentation for this scenario.

Question 4 — Hematology/Myeloproliferative Disorders

A 60-year-old man with a history of chronic liver disease presents to the clinic complaining of generalized itching (pruritus) that worsens after showering. Physical examination reveals a ruddy complexion, and his complete blood count shows marked erythrocytosis (elevated hemoglobin and hematocrit). Genetic testing confirms a mutation in the JAK2 gene. What is the most likely diagnosis?

A) Primary Myelofibrosis
B) Polycythemia Vera
C) Essential Thrombocythemia
D) Chronic Myeloid Leukemia (CML)
E) Acute Megakaryoblastic Leukemia

Answer: B. The combination of erythrocytosis, pruritus, and the presence of a JAK2 mutation is pathognomonic for Polycythemia Vera (PV). PV is a myeloproliferative neoplasm characterized by excessive production of red blood cells. While CML also involves the Philadelphia chromosome (BCR-ABL), PV is defined by its erythrocytosis and specific genetic marker (JAK2 V617 F mutation).

Quick fire review

What constellation of findings strongly suggests DIC?

Thrombocytopenia, elevated PT/BT, low fibrinogen, schistocytes, and massively elevated D-dimer.

In the setting of a dead fetus or amniotic fluid embolism, what is the primary mechanism leading to DIC?

Release of substances into circulation that cause massive activation of the coagulation cascade.

What is the key difference in bleeding presentation between a platelet disorder and a factor deficiency?

Platelet disorders cause superficial/mucosal microhemorrhages; Factor deficiencies cause deep, major hemorrhage (e.g., hemarthrosis).

Which specific receptor binding to sheughan-like toxin initiates TTP/HUS pathology?

The GB3 receptor, found predominantly on endothelial cells.

What is the preferred treatment for TTP/HUS?

Plasma exchange (PLEX) or fresh frozen plasma (FFP).

Which factor deficiency causes a bleeding pattern that might be missed if only looking at PT and PTT?

Factor XIII deficiency, which can present with major bleeds in young children despite normal initial coagulation screens.

What is the classic lab finding associated with DIC due to fibrinolysis?

Massively elevated D-dimer (D-dimer reflects breakdown of fibrin).

Which specific factor deficiency causes Hemophilia C, and what is its inheritance pattern?

Factor XI deficiency; inherited in a non-X-linked recessive fashion.

What molecular mutation is most commonly associated with Polycythemia Vera?

JAK2 mutation.

In TTP/HUS, which receptor binding initiates endothelial damage?

Sheughan-like toxin binding to the GB3 receptor.

Which condition presents with a combination of thrombocytopenia, MAHA (schistocytes), and AKI?

Thrombotic Microangiopathy (TMA), specifically TTP or HUS.

What is the primary difference in bleeding presentation between Glanzmann thrombasthenia and Hemophilia A?

Glanzmann's causes mucosal bleeds; Hemophilia A causes deep tissue/joint bleeds.

Quick recall / Anki-style questions