SPEAKER_00 0:00

Have you ever taken a medical test? Maybe just something routine. And uh your doctor looks at the results, pauses, and says those dreaded words. Well, your numbers are borderline.

SPEAKER_01 0:11

Oh, yeah, the absolute worst.

SPEAKER_00 0:13

Right. I mean, how did that make you feel? Did you feel completely normal, or did you suddenly feel like, I don't know, a ticking time bomb just waiting for some biological tripwire to snap?

SPEAKER_01 0:22

Yeah, it is a completely destabilizing word, borderline.

SPEAKER_00 0:26

It really is.

SPEAKER_01 0:27

Because it just strips away the comfort of certainty. You know, you walk into the clinic hoping for a binary answer like you are sick or you are well. And instead, they hand you a question mark. You're told you live in this gray zone.

SPEAKER_00 0:40

Exactly. You're left sitting on the exam table wondering, uh, do I have a disease? Do I have a risk factor? Or wait, am I totally fine?

SPEAKER_01 0:48

Yeah, exactly.

SPEAKER_00 0:49

And that uncomfortable kind of murky space is exactly what we are exploring in today's deep dive. We're looking at this fascinating concept of diagnostic borderlands.

SPEAKER_01 0:57

It's such a great term for it.

SPEAKER_00 0:58

Yeah, it's from a really insightful piece by William Ayrd titled The Borderlands of Diagnosis: Living Between Variation and Disease. And our mission today is to explore the messy friction between human biology, which operates on this continuous flowing spectrum, and medical diagnosis, which, as we know, absolutely demands neat categorical yes or no boxes.

SPEAKER_01 1:21

Right. Because biology simply refuses to be categorized neatly. It doesn't care about our boxes.

SPEAKER_00 1:27

No, it really doesn't.

SPEAKER_01 1:28

So to illustrate this, we're going to look at one of the most compelling case studies in all of medicine for this problem, which is von Villebrand disease or VWD.

SPEAKER_00 1:37

Okay, let's unpack this. Because to really understand this friction, this borderland, we first have to examine why the border was drawn in the first place, right? Before we get into the abstract stuff, what is this disease actually doing in the body?

SPEAKER_01 1:48

Okay, so think about what happens when you get a cut. To stop the bleeding, your body relies on a crucial protein in your blood called von Willebrand factor or VWF.

SPEAKER_00 1:57

Got it. So VWF.

SPEAKER_01 1:59

Right. You can visualize VWF as um kind of like a molecular velcro. It constantly circulates in your bloodstream. And when a blood vessel is damaged, it immediately binds to the exposed collagen in the vessel wall.

SPEAKER_00 2:12

Aaron Ross Powell Like it's anchoring itself to the injury.

SPEAKER_01 2:14

Precisely. And then it catches passing platelets, sticking them together to form the initial plug. Oh. And on top of that, it actually acts as a protective carrier for another vital clotting protein called factor eight. It basically keeps factor eight from breaking down too quickly in the bloodstream.

SPEAKER_00 2:31

Aaron Powell So it's essentially the primary tether line of the circulatory system. If you don't have enough of this Velcro, the platelets just wash right past the injury and you keep bleeding.

SPEAKER_01 2:41

Aaron Powell That is the core mechanism of type 1 VWD, which is by far the most common form of the disorder. Okay. It's what we call a quantitative defect, meaning your body produces perfectly normal VWF, but just not enough of it. Right. And here is where the borderland emerges. The amount of this molecular velcro varies wildly across the general population. It is not a fixed universal number for everyone.

SPEAKER_00 3:02

Aaron Powell Just a huge spectrum.

SPEAKER_01 3:04

Aaron Ross Powell Exactly. So the medical community has to draw a line in the sand to dictate who gets treatment. They measure the protein's activity and concentration using these standardized metrics, specifically international units per deciliter or IUDL. Trevor Burrus, Jr.

SPEAKER_00 3:18

Right, the lab numbers.

SPEAKER_01 3:19

Aaron Powell Yeah. And for decades, doctors have used these very specific cutoffs at 30 IUDL and 50 IUDL to organize care.

SPEAKER_00 3:27

Trevor Burrus Okay, so I want to challenge the rigidity of those numbers for a second. Go for it. Because it feels a bit like well, like structural load limits in architecture or even just a highway speed limit. Trevor Burrus, Jr.

SPEAKER_01 3:37

Oh, speed limits is a great way to think about it. Trevor Burrus, Jr.

SPEAKER_00 3:39

Right. Because let's say you're driving 56 miles per hour in a 55 zone, you get a ticket. But at 54 miles per hour, you don't. The physical speed, the actual danger, is basically identical.

SPEAKER_01 3:49

Trevor Burrus, Jr.: Completely indistinguishable, really.

SPEAKER_00 3:51

Trevor Burrus, Jr.: Yeah. But the legal consequence is vastly different. So if a patient with a VWF level of, say, 49 IUDL gets a disease label, and a patient at 51 IUDL doesn't, aren't we just pretending these numbers represent biologically different states?

SPEAKER_01 4:06

What's fascinating here is that you have hit on the exact tension that drives hematologists completely crazy.

SPEAKER_00 4:12

Really?

SPEAKER_01 4:13

Oh yeah. Because you're right. A level of 49 and 51 do not represent biologically different states. The person at 49 isn't suddenly falling off a physiological cliff.

SPEAKER_00 4:24

Right. Their blood isn't behaving entirely differently over two points.

SPEAKER_01 4:27

Exactly. But clinically, they are treated completely differently. You have to realize that thresholds are tools. They are not truths in nature.

SPEAKER_00 4:37

Aaron Ross Powell So why rely on them so heavily if they are biologically arbitrary? I mean, why not just treat the symptom?

SPEAKER_01 4:43

Because without those hard numbers, the entire healthcare apparatus basically grinds to a halt.

SPEAKER_00 4:48

Really? Just stops.

SPEAKER_01 4:49

Pretty much. Think about research. Research becomes impossible because you can't group patients into standard cohorts to study new treatments.

SPEAKER_00 4:57

Well, sure, you need a defined group.

SPEAKER_01 4:58

Right. And then insurance coverage becomes wildly inconsistent.

SPEAKER_00 5:01

Right, the billing codes.

SPEAKER_01 5:03

Exactly. Or think about a surgeon. A surgeon needs a definitive protocol to know if they should prepare for catastrophic bleeding during an operation. They need a yes or no. So the threshold is an absolute practical necessity, but it creates this stubborn illusion of a hard biological boundary.

SPEAKER_00 5:20

Aaron Powell Which doesn't really exist. And because that single point on a test dictates your care, deciding exactly where to place that line becomes this massive clinical and honestly ethical debate.

SPEAKER_01 5:33

It's a huge debate.

SPEAKER_00 5:35

It's not just an objective science problem anymore, it's a policy problem.

SPEAKER_01 5:38

Aaron Powell Totally. It becomes a debate over what kind of error the medical community is more comfortable making.

SPEAKER_00 5:42

Aaron Powell Wait, what do you mean by what kind of error?

SPEAKER_01 5:44

Oh, are we more comfortable overdiagnosing healthy people or underdiagnosing sick people? Oh, I see. And you see this clash perfectly illustrated in recent medical guidelines. In 2021, a coalition of major international blood societies, so this includes the American Society of Hematology, the World Federation of Hemophilia, big players, they released diagnostic guidelines that placed a massive value on access to care.

SPEAKER_00 6:07

Aaron Ross Powell Okay, so they were trying to build a wider safety net for patients.

SPEAKER_01 6:10

Yes. For patients who had a history of abnormal bleeding symptoms, these societies actually lowered the threshold. They recommended diagnosing type 1 VWD in any symptomatic patient with a VWF level below 50 IUDL. So they explicitly chose to risk slightly over-diagnosing people to ensure that anyone experiencing debilitating bleeds could get access to treatment and get their insurance to pay for it.

SPEAKER_00 6:36

Let me push back on that 2021 guideline, though. Sure. Because if we lower the diagnostic threshold just to ensure insurance companies will pay for a patient's care, aren't we kind of corrupting the actual science?

SPEAKER_01 6:49

Aaron Powell It's a very fair question.

SPEAKER_00 6:51

I mean, it sounds like we're muddying the biological definition of a disease just to cheat a broken administrative system.

SPEAKER_01 6:56

Aaron Powell That is precisely the counterargument. And it leads directly into the backlash we saw just a few years later.

SPEAKER_00 7:01

Aaron Powell Oh, there was backlash.

SPEAKER_01 7:02

Yeah. Fast forward to 2024, and the British Society for Hematology released their own laboratory guidelines. And they took a much more cautious, scientifically rigorous approach. They urged extreme caution in that exact 30 to 50 IUDL graze zone. They didn't want to just hand out the diagnosis automatically.

SPEAKER_00 7:22

What was their biological reasoning for disagreeing so sharply with the American and international groups?

SPEAKER_01 7:27

Their perspective is that the biological correlation between your VWF level and your actual bleeding risk in that middle zone, that 30 to 50 range, is incredibly weak.

SPEAKER_00 7:38

Interesting.

SPEAKER_01 7:38

Yeah. Imagine a patient in that borderline range who is suffering from severe nosebleeds. The British guidelines argue that the VWF level might just be a bystander.

SPEAKER_00 7:49

Like it's a coincidence.

SPEAKER_01 7:50

Exactly. The bleeding could actually be caused by an entirely different unidentified platelet defect or maybe a localized vascular issue in the nose. Right. If you slap a Von Willebrand disease label on that patient simply because their number is, say, 45, you anchor the doctor's mindset.

SPEAKER_00 8:06

Oh wow. The doctor stops looking for the actual cause of the bleeding.

SPEAKER_01 8:10

Yes. You essentially blind the medical team to other possibilities by giving them a convenient answer.

SPEAKER_00 8:15

That makes total sense. But and here's the other side of that. Denying that label isn't a neutral act either.

SPEAKER_01 8:20

No, not at all.

SPEAKER_00 8:21

Because the diagnosis basically operates as a passport.

SPEAKER_01 8:24

A passport, yeah, that's a perfect word for it.

SPEAKER_00 8:26

If you get the label, you get the passport. It grants you entry to specialized hematology follow-ups, it gets you robust surgical planning, it gets a teenager school accommodations for heavy periods.

SPEAKER_01 8:37

Absolutely.

SPEAKER_00 8:38

It validates you. It tells the patient, you're not crazy. Your history of bleeding has a name.

SPEAKER_01 8:44

It makes your physical suffering legible to a doctor who has never met you before. You don't have to sit there and retell your story and prove you're sick from scratch every single time you enter a new clinic.

SPEAKER_00 8:54

Exactly. But if you follow the strict British guidelines, what happens to the patient sitting in the exam room who misses the cutoff by one single point?

SPEAKER_01 9:03

They encounter one of the most distressing phrases in all of medicine. Which is not abnormal enough.

SPEAKER_00 9:10

Ugh, that's brutal.

SPEAKER_01 9:11

It is. You have a patient who suffers from severe menstrual bleeding. Maybe they're soaking through clothes, missing work or school, but because their lab number is 52 instead of 49, their access to care becomes incredibly precarious.

SPEAKER_00 9:24

They lose the passport.

SPEAKER_01 9:25

They lose it. Their bleeding is very real, but they just didn't clear the administrative hurdle.

SPEAKER_00 9:30

And what makes this threshold dilemma infinitely more frustrating for that patient is that the test number itself refuses to sit still, right? It's a moving target.

SPEAKER_01 9:41

Oh yes. The lab number is incredibly vulnerable to context. Your VWF levels fluctuate based on stress, exercise, and systemic inflammation.

SPEAKER_00 9:51

Wait, really? Yeah. Like everyday stressors can physically change the amount of clotting protein in your blood.

SPEAKER_01 9:57

Absolutely. VWF is what we call an acute phase reactant. When your body senses physical stress, it releases more of the protein into your bloodstream as a protective mechanism. It's essentially preparing for potential injury.

SPEAKER_00 10:09

So if I have a bad cold or I just ran up a flight of stairs before my blood draw, my number will spike.

SPEAKER_01 10:14

It will spike. Yeah. You could test normal on Tuesday and borderline on Thursday just based on your commute.

SPEAKER_00 10:19

That is wild.

SPEAKER_01 10:20

But the biological variables go even deeper than just a temporary stress response. Your actual blood type fundamentally alters your baseline.

SPEAKER_00 10:28

My blood type. Like ABO.

SPEAKER_01 10:30

Yes. People with blood group O naturally have VWF levels that are 25 to 30% lower than people with blood types A, B, or A B.

SPEAKER_00 10:40

Why does your blood type have anything to do with a clotting protein?

SPEAKER_01 10:43

It all comes down to molecular clearance rates.

SPEAKER_00 10:46

Okay, tell me more.

SPEAKER_01 10:47

So without getting too deep into the biochemistry, the VWF protein in your blood has these complex sugar molecules attached to it, and those sugars correspond to your ABO blood type. Okay. People with blood type O lack certain specific sugar antigens on that protein. And because those sugars are missing, enzymes in the bloodstream recognize the protein differently and they clear it out of the circulation much faster.

SPEAKER_00 11:10

Oh wow. So a patient with type O blood is actively filtering the molecular velcro out of their system faster.

SPEAKER_01 11:18

Exactly.

SPEAKER_00 11:18

Pushing them closer to the disease threshold, literally from birth.

SPEAKER_01 11:21

Yes. And that raises a huge debate about whether we should have completely different diagnostic thresholds based on blood type.

SPEAKER_00 11:27

I would think so.

SPEAKER_01 11:28

But the most significant life-altering shifts in these numbers happen over time, specifically with aging and pregnancy.

SPEAKER_00 11:34

How does age affect it?

SPEAKER_01 11:36

Well, VWF is stored in the endothelial cells. Those are the cells that line the inside of your blood vessels. Okay. As we age, natural vascular changes cause those cells to release more VWF into the bloodstream. So your baseline level just naturally creeps up as you get older.

SPEAKER_00 11:51

And what about during pregnancy?

SPEAKER_01 11:53

During pregnancy, surging estrogen levels act as a master switch. They trigger massive releases of VWF. The body is essentially stockpiling clotting factor to protect the mother from catastrophic bleeding during childbirth.

SPEAKER_00 12:06

Here's where it gets really interesting. Think about what this means for a patient's identity.

SPEAKER_01 12:11

Right.

SPEAKER_00 12:11

Let's say a person is diagnosed with type 1 VWD as a teenager, because they test it at 40 IUDL.

SPEAKER_01 12:18

Okay, solid diagnosis.

SPEAKER_00 12:19

They carry this label their whole life, this identity of being someone with a bleeding disorder. But when they are retested in their 40s, their natural aging process has pushed their levels up to 60 IUDL, which is firmly in the normal range. Yes. Doesn't undiagnosing someone in their 40s just gaslight them about their own lived experience? I mean, if aging naturally raises the lab result, does it actually cure the underlying patient?

SPEAKER_01 12:44

That is such a vital distinction, and misinterpreting it is a major danger in clinical practice. The first test a patient takes isn't a permanent definition of their biology, it is a time stamp.

SPEAKER_00 12:56

A time stamp? I like that.

SPEAKER_01 12:58

It just captures their physiology at that specific moment. Take pregnancy, for example. If a woman's levels normalize during her third trimester because of estrogen, that is a physiologic masking effect. It is temporary. It is absolutely not curative because after delivery, her hormones shift, her VWF levels crash back down, and she is suddenly at extreme risk for severe postpartum hemorrhage.

SPEAKER_00 13:21

So the disease was just hiding behind the estrogen.

SPEAKER_01 13:23

Exactly. And the same logic applies to aging. Rising levels in older age do not erase a patient's historical physiology. If you bled heavily for 20 years, the fact that your lab number crosses the 50 IUDL threshold today doesn't mean your doctors were wrong back then. Removing a disease label shouldn't erase a patient's story. It just requires the doctor to explain the story better.

SPEAKER_00 13:45

Okay, so if the label is just a timestamp and the numbers are constantly bouncing around based on your blood type, your age, and whether you just walk up a flight of stairs. How should doctors and patients actually think about the risk of bleeding?

SPEAKER_01 13:59

It's tough.

SPEAKER_00 14:00

It sounds like the binary idea of sick versus healthy completely falls apart here.

SPEAKER_01 14:04

It really does. We have to adopt a total paradigm shift. We have to move from thinking about this as a state of constant sickness to a state of conditional vulnerability.

SPEAKER_00 14:14

Conditional vulnerability, meaning my biology is perfectly adequate for sitting here at a desk, but it might fail me if I get into a car accident.

SPEAKER_01 14:22

You nailed it. For many people in these diagnostic borderlands, VWD isn't a constant daily impairment. They go through ordinary life completely fine. But their clotting system fails during what we call hemostatic challenges.

SPEAKER_00 14:35

Hemostatic challenges. What counts as one of those?

SPEAKER_01 14:38

Here's our basically physical stress tests for the body. Things like childbirth, having a wisdom tooth extracted, major surgery, or severe trauma. The risk is highly situational.

SPEAKER_00 14:49

Let's ground this in reality for a second. Think about a nine-year-old boy.

SPEAKER_01 14:53

Okay.

SPEAKER_00 14:53

He has borderline VWF levels, maybe hovering right around 46 to 54 IUDL, and he has blood group O, which explains the lower baseline, plus he gets frequent nosebleeds.

SPEAKER_01 15:06

A very common scenario.

SPEAKER_00 15:07

Normally, a doctor might hesitate to slap a lifelong heavy disease label on a child based on borderline numbers.

SPEAKER_01 15:14

And that clinical hesitation makes complete sense. You don't want to needlessly medicalize a child's life or panic the parents over something they might outgrow or never really suffer from.

SPEAKER_00 15:24

Right. But in this specific scenario, let's say the boy is facing a tonsilectomy next week.

SPEAKER_01 15:28

Oh, well, that changes everything. Right.

SPEAKER_00 15:30

A tonsilectomy is a massive hemathatic challenge. The tissue in the throat is highly vascular.

SPEAKER_01 15:35

It's an incredibly bloody surgery.

SPEAKER_00 15:37

So he might not need the permanent identity of a VWD patient today, but he absolutely needs a surgical plan right now. Exactly. There's a phrase from the source material that perfectly captures this. Unexposed does not mean unaffected. Just because he hasn't had a major surgery yet doesn't mean his borderline numbers are harmless.

SPEAKER_01 15:56

And this concept of conditional vulnerability, it also echoes through entire families, which brings us to another incredible dynamic in the borderlands.

SPEAKER_00 16:04

Oh, how so?

SPEAKER_01 16:05

Consider a 13-year-old girl who gets diagnosed after suffering from severe, heavy menstrual bleeding.

SPEAKER_00 16:10

Okay, so you get the official diagnosis.

SPEAKER_01 16:13

Right. And her diagnosis suddenly reorganizes her entire family's memory.

SPEAKER_00 16:17

Oh wow. I can see that.

SPEAKER_01 16:18

Her mother looks at the teenager's diagnosis and suddenly remembers her own terrible periods in her twenties, which she just assumed were a normal part of womanhood.

SPEAKER_00 16:27

Because nobody ever attested her.

SPEAKER_01 16:28

Exactly. And they look further back and realize the grandmother had a mysterious early hysterectomy at age 38, likely because her doctors couldn't control her bleeding.

SPEAKER_00 16:37

So if we connect this to the bigger picture, a diagnosis in the borderlands rarely applies only to the individual in the room.

SPEAKER_01 16:45

Never just the individual.

SPEAKER_00 16:46

It moves backward through time, rewriting family history, and it moves outward through the family tree. But that revelation has to carry an immense psychological weight. I mean, the mother often asks tearfully, Did I give this to her?

SPEAKER_01 17:01

Which is such a deeply human protective reaction. You see it all the time.

SPEAKER_00 17:05

Yeah, it breaks your heart a little.

SPEAKER_01 17:07

It does. But the crucial lesson hematologists try to impart is that genetic inheritance is not a fault. Right. Genes are transmitted. They are not assigned with malicious intent. The purpose of mapping out a family's bleeding history isn't to assign blame or to suddenly create a whole family of anxious, over-medicalized patients.

SPEAKER_00 17:26

I don't know. What is the goal?

SPEAKER_01 17:27

It's simply gathering data that can protect the next person in line. If the family knows this genetic tendency exists, the next time someone needs their appendix out or gets pregnant, the surgical team can be prepared.

SPEAKER_00 17:38

So, what does this all mean for you, the listener? What is the practical takeaway when we wade through all these shifting variables? It seems to me that when you are operating in the borderlands, the most important question a doctor can ask isn't, what is the perfect scientifically pure label for this patient? Yeah, yeah. The real question is, what is the safest plan for this specific situation?

SPEAKER_01 17:58

That is the ultimate synthesis. Medical thresholds, these cutoff numbers at 30 or 50 IUDL, they are ethically and practically necessary. We need them to organize our healthcare system and conduct research.

SPEAKER_00 18:12

You can't function without them.

SPEAKER_01 18:13

We really can't. But we must constantly remind ourselves that they're just decision-making tools. They are not measures of absolute biological truth, and they certainly are not measures of a patient's suffering. Yeah. The number on the lab report should guide the clinical care, but it should never invalidate the patient's lived experience.

SPEAKER_00 18:30

We started this deep dive talking about that terrifying feeling of getting a borderline test result, the anxiety of not fitting neatly into a box. And through the lens of VWD, we've seen how complex the space between normal and diseased really is. It isn't a sharp line, it's a whole landscape.

SPEAKER_01 18:47

A landscape defined by molecular clearance rates, hormonal shifts, timing, and uh individual vulnerability.

SPEAKER_00 18:54

Which brings us back to that powerful idea. Unexposed does not mean unaffected. Medicine relies heavily on bleeding assessments and historical questionnaires. A doctor might completely miss someone's underlying vulnerability simply because that person hasn't faced a major challenge like a car crash or a childbirth yet.

SPEAKER_01 19:12

They just haven't been tested by life.

SPEAKER_00 19:14

Right. So I want to leave you with a final thought to mull over. Consider your own health and the health of your family. If so much of a disease like this is about conditional vulnerability remaining completely invisible until a specific stressor forces it into the light, what hidden borderlands might you be living in right now?

SPEAKER_01 19:31

It's a profound question.

SPEAKER_00 19:32

If health is purely situational, maybe none of us are permanently normal. We just haven't met our biological trigger yet. Keep asking questions, keep exploring the gray areas, and we will see you next time on the deep dive.