The Clot Thickens: Why Cholesterol Isn’t the Prime Culprit in Atherosclerosis

Nutrition Network’s Registered Dietitian and Head of content, Tamzyn Murphy, interviews Dr Malcolm Kendrick ,GP and author of the book making waves in the cardiovascular space: The Clot Thickens. Dr Kendrick features in the latest Nutrition Network Course – Cardiovascular Health.

For decades, the cholesterol (more precisely, LDL-C) story has dominated our understanding of atherosclerosis. Eat saturated fat → cholesterol rises → cholesterol seeps into artery walls → plaques grow → a chunk breaks off → heart attack or stroke. Clean and compelling.

Dr Malcolm Kendrick argues it’s also wrong.

In our recent live discussion, Kendrick laid out—patiently, humorously, and with a physiologist’s insistence on mechanism—why the lipid-heart narrative doesn’t survive contact with biology. In its place, he describes a simpler, more coherent model: atherosclerosis is fundamentally a disease of endothelial injury, localized clotting, and imperfect repair.

Below, we’ll walk through the key challenges he raised to the idea that LDL causes atherosclerosis, then build the case for clotting as the obvious process behind it. We’ll end with practical strategies that reduce endothelial damage and support vascular repair.

The Classic Story—and Why It’s Seductive

Dr Kendrick began by sketching the orthodox view: “You eat too much cholesterol… The cholesterol in your blood goes up. It gets absorbed into your artery walls. They thicken and narrow, and that causes heart attacks and strokes.” He’s the first to admit why this narrative stuck. It’s intuitive, easy to teach, and lines up with early pathology images showing “cholesterol” within plaques.

But biology isn’t obliged to honor our intuitions. When you follow the steps one by one—how lipids move, how arteries are built, how clots form and resolve—the story frays.

First Principles: What’s Actually in the Bloodstream?

We don’t have free “cholesterol” sloshing around in our blood. Blood is water-insoluble. So the body packages cholesterol (with fats) into lipoproteins—tiny “taxis” with recognizable protein addresses. Kendrick notes: “Cholesterol and fats are taxied together… in a small sphere… the lipoproteins.” The LDL particle is one such taxi.

This matters because the lipid-heart story assumes LDL can physically cross the endothelial cell layer, accumulate below it, and kick off plaque formation. That brings us to anatomy and scale.

The Arterial Wall Is Not a Leaky Sponge

Imagine your garden hose delivering water to a sprinkler. If water seeped out everywhere along the hose, the sprinkler would sputter. Large arteries are the body’s hoses: they’re built to not let the contents leak. As Kendrick put it, the endothelium (the cell lining) is tied together by tight junctions—“a concrete reinforced wall to stop that happening.”

He drives the point home with scale. If an atom were the size of a human being, an LDL particle would be “the size of a large sports stadium.” Atoms cannot drift through tight junctions unless a cell actively opens the gate. Expecting a “stadium” to push between cells, cross a half-mile-in-scale cell interior, and exit the far side without using the LDL receptor machinery runs counter to how multicellular life stays alive.

“Without tight junctions, there would be no possibility of multi-celled organisms living.”

Implication: the default state of healthy artery lining is impenetrable to LDL from the lumen side. If LDL is found within the wall, a different pathway (or a damaged lining) is involved.

The “Back Door” No One Talks About

Here’s a twist: arteries big enough to develop plaques come with their own micro-blood supply—tiny vessels called the vasa vasorum (“vessels of the vessels”). These capillaries nourish the artery wall from the outside, and unlike the lumen-facing endothelium, they have fenestrations—little windows that allow exchange.

Translation: anything in blood, including LDL, can enter the arterial wall from the adventitial side via vasa vasorum. That alone breaks the simple “LDL must ooze in from the lumen” story. And it raises an awkward question: if passive LDL seepage into walls were plaque-forming, why don’t veins—bathed in the same LDL—develop atherosclerosis?

Why arteries and not veins?

It’s not LDL concentration; it’s local injury and hemodynamic stress. Arteries carry pulsed, high-pressure flow with areas of turbulence (branch points, curves) that are more injury-prone. Veins live in a lower-pressure world—and when they do get arterialized (e.g., bypass grafts), they start to develop arterial-type atherosclerosis. The variable is mechanical/biological injury, not “LDL presence.”

Twelve Angry Molecules: The Case That Falls Apart on Inspection

Kendrick compares the momentum of the lipid-heart narrative to the film Twelve Angry Men: a pile of “obvious” facts that crumble under scrutiny. Three of his most potent challenges:

1. Barrier biology: Healthy endothelium is not passively permeable to large particles. “We’re supposed to believe… LDL is popping through and into the cells, popping out the back… with processes that are not found in nature.”
2. Distribution problem: If LDL seepage causes plaques, why the patchiness? Why specific arterial spots and not a uniform thickening across all vessels—including veins?
3. Growth pattern: Plaques don’t enlarge smoothly year after year. In longitudinal imaging studies they jump in size—quiet periods punctuated by step-ups. That’s exactly what you’d expect from episodic clots that get incorporated into the wall, not slow LDL seepage.

“But We See Cholesterol in Plaques!”

We do. The key is what kind.

• LDL mostly carries cholesterol esters (cholesterol joined to a fatty acid).
• The striking needle-like cholesterol crystals pathologists photograph are free cholesterol, not esters.

Where in the body is free cholesterol abundant enough to crystallize? Kendrick’s answer: red blood cell membranes. That points directly to clot material. When you find crystals, you’re likely looking at the remains of red cells that were part of a thrombus, not LDL “leaked” from plasma.

He adds another layer: Lipoprotein(a), or Lp(a), is essentially LDL with an added apo(a) protein. That add-on inhibits clot breakdown (it blocks tissue plasminogen activator), and Lp(a) sticks to vascular injuries. If you look for the apo(a) tag, you find it in plaques. That’s a clot story, not an LDL-seepage story.

Meet the Glycocalyx: Your Blood Vessels’ Slippery Shield

One of Kendrick’s most helpful metaphors is a fish. Try to hold a freshwater fish and it seems to “run” out of your hands. That slime layer is the glycocalyx—a sugar-protein gel that makes surfaces ultra-slippery.

We have tennis-courts’ worth of glycocalyx lining our vasculature. It’s antithrombotic, reduces friction, produces nitric oxide, and protects the endothelium from the chemical and mechanical stress of flowing blood. As Kendrick put it, “It makes Teflon look sticky.”

When the glycocalyx thins or tears, the cells beneath are exposed, vulnerable, and easier to injure. That’s when the clot-and-repair cycle begins.

A Better Fit: Injury → Clot → Cover → Incorporate → Repeat

Kendrick’s model is refreshingly anatomical:

1. Endothelial injury occurs (often because the glycocalyx is stripped or thinned).
2. A clot forms on that spot to seal the breach—because inside the body, you can’t afford a freely shedding scab that will embolize downstream.
3. Endothelial progenitor cells circulate to the site and re-sheet the surface—sealing the clot beneath the lining.
4. The body’s cleanup crew—macrophages and fibrinolysis—tries to remodel and remove the clot.
5. Usually the remodeling succeeds; sometimes (big clot, tough fibrin, plenty of Lp(a), impaired cleanup) remnants persist.
6. The same spot—now structurally altered—becomes a magnet for the next micro-injury and the next micro-clot.

Over years, you get layered growth—like tree rings. This is exactly what plaque histology often shows: strata that mirror repeated injury-and-repair, not a single, steady ooze of fat.

“Plaques are basically blood clots in disguise or in different stages of repair and transformation.”

Why does calcium appear?

Think of Kendrick’s “cut-arm-on-the-roof” story. Scar tissue on his wrist is white years later because it’s calcified—the end stage of tissue repair. So too in arteries: old, stabilized plaques often calcify. That’s a healed injury marker, not evidence of calcium “leaking in” from the lumen.

When Biology Bites: Sepsis, Viruses, and Autoimmunity

If this model is right, then conditions that strip glycocalyx, injure endothelium, promote clotting, or impair repair should elevate cardiovascular risk. They do.

• Sepsis: bacterial toxins shatter glycocalyx and endothelium; disseminated intravascular coagulation forms clots everywhere. Survivors can lose digits or limbs from vascular occlusions.
• SARS-CoV-2: the virus binds ACE2 on endothelial cells, triggering cell death and a hyper-clotting state.
• Autoimmune vasculitides (e.g., lupus with antiphospholipid antibodies): the immune system targets vessel walls and the clotting apparatus. Kendrick highlights an eye-opening statistic: young women with lupus may see a ~50-fold (5,000%) increase in risk.
• Sickle cell disease: misshapen red cells physically damage the lining; severe atherosclerotic-like lesions and vascular occlusions can appear in childhood.

None of these increase LDL; all increase injury/clotting load.

The LDL Detour: What About Lean-Mass Hyper-Responders?

Kendrick discussed the subgroup whose LDL rises sharply on very low-carb diets. His take centers on liver physiology:

• Most LDL in blood is the end-product of VLDL secreted by the liver when it must convert excess carbohydrate into fat (de novo lipogenesis).
• On carb-restricted diets, fat travels from the gut primarily via chylomicrons (through the thoracic duct to systemic veins), not through the liver as VLDL.
• In some lean individuals, the liver appears to down-regulate LDL receptor uptake because it doesn’t need to reclaim the expensive protein “hardware” from LDL when it isn’t building much VLDL.

Hence, LDL rises—not because more fat equals more LDL taxis, but because of receptor-level control. He underscores hepatic control by pointing to homozygous familial hypercholesterolemia: children with virtually no LDL receptors have sky-high LDL; liver transplantation normalizes LDL immediately.

Whatever one concludes about risk in this subgroup, it doesn’t rescue the “LDL oozes in to start plaques” model. The initiating event still must respect barrier biology, injury localization, and clot-integration dynamics.

The Reasons LDL-C Cannot Be the Primary Initiator—Laid Out

To crystallize Kendrick’s argument, here are the key “why not LDL” points:

1. Barrier Integrity: Healthy endothelium with intact tight junctions is not passively permeable to large lipoproteins. The idea that LDL “pushes through” between cells is mechanistically implausible and incompatible with multicellular survival.
2. Receptor Reality: Cells that need LDL express LDL receptors to import it purposefully. A paracellular, receptor-bypassing “ooze” would render receptor biology redundant.
3. The Back Door Exists: The vasa vasorum allows plasma contents (including LDL) into the arterial wall from the outside; thus, “lumen seepage” is unnecessary—and does not explain where plaques form.
4. Veins Don’t Plaque: If plasma LDL exposure were sufficient, veins (which share the same LDL milieu) should develop atherosclerosis—they don’t, unless arterialized.
5. Patchiness and Hemodynamics: Plaques appear at high-stress sites (branch points, curves), consistent with injury hotspots, not with uniform lipid exposure.
6. Phasic Growth: Plaques enlarge in jumps, consistent with episodic clot-then-incorporate, not gradual lipid accumulation.
7. Cholesterol Crystals’ Origin: The free cholesterol needles seen in plaques most plausibly come from red blood cells within clots, not from LDL’s cholesterol esters.
8. Lp(a) Fingerprint: Lp(a) preferentially binds injured sites and resists fibrinolysis; its presence in plaques supports a thrombotic (not seepage) origin.
9. Risk Factor Coherence: Conditions that raise risk (smoking, hyperglycemia/diabetes, toxins, autoimmune vasculitis, infections like sepsis/COVID, hypertension, chronic stress) are all injury/clotting/repair problems—not LDL exposure problems.

Together, these points make a simple claim: LDL-C is neither necessary nor sufficient to initiate atherosclerosis. The initiating and propagating engine is localized vascular injury, clot formation, and imperfect repair.

The Slippery Shield and the Scab You Never See

Two of Kendrick’s analogies help the clot-repair model snap into place:

• The fish you can’t hold: that slippery coat is glycocalyx—our vessels’ anti-clot Teflon. When it’s stripped, damage follows.
• The rooftop cut: when you cut your skin, it clots, scabs, and later calcifies into a pale scar. Inside arteries, a scab can’t be allowed to flake off, so the body covers it with new endothelium and incorporates it into the wall. Over time, repeated cycles leave layers; old scars calcify.

Once you see plaques as healed/half-healed clots, many incongruities of the cholesterol story disappear.

Reframing Risk: Three Levers That Matter

Kendrick groups drivers of atherosclerosis into three interacting levers:

1. How much endothelial damage you cause (e.g., smoking, glycemic spikes, toxins, turbulent flow, high BP, infections).
2. How big the clots are when damage occurs (pro-thrombotic states, high Lp(a), inflammatory milieu).
3. How well you repair and remodel (glycocalyx regeneration, nitric oxide availability, endothelial progenitor cell function, effective fibrinolysis).

Lower the damage, shrink the clots, and enhance repair—and you shift the whole system toward vascular resilience.

Practical Strategies: Reduce Injury, Limit Clot Burden, Support Repair

Kendrick’s closing advice is strikingly practical. None of it requires a PhD to implement; all of it maps directly to the injury–clot–repair model.

1) Reduce endothelial injury

• Don’t smoke. Even a single cigarette causes measurable endothelial injury: “After they smoke one cigarette… dead endothelial cells can be detected immediately.”
• Tame glucose excursions. High-glucose meals thin the glycocalyx for hours; low-glycemic patterns help preserve it.
• Minimize toxin exposure. Wood smoke, diesel nanoparticles, and certain heavy metals can reach blood and injure the lining.
• Treat infections promptly. Sepsis ravages the glycocalyx and induces body-wide clotting; vaccination and early care reduce catastrophic “clot storms.”
• Manage blood pressure and flow turbulence. Treat hypertension; prioritize movement patterns and aerobic fitness that support vascular health.

2) Limit clot size when injury occurs

• Address inflammatory burden. Autoimmune activity and chronic inflammation increase thrombotic tendency; work with clinicians on targeted therapy and lifestyle inputs.
• Be mindful of Lp(a). You can’t change your genotype, but recognizing elevated Lp(a) underscores the importance of minimizing endothelial hits (smoking, sugars, toxins) and optimizing repair.

3) Improve repair capacity

• Sunlight exposure. “People who sunbathe, their risk of death is vastly reduced…” Sensible sun boosts nitric oxide, supports metabolic health, and correlates with better outcomes. Don’t burn; aim for regular, brief exposures.
• Move—especially some intensity. Exercise improves insulin dynamics, NO signaling, and endothelial function.
• Nutrient sufficiency. Kendrick mentions vitamin D and vitamin C (he takes ~1 g/day) as part of a general repair-supportive stance.
• Avoid unnecessary long-term steroids/immunosuppressants. They’re anti-inflammatory yet paradoxically increase CVD risk—in part by impairing repair. If you must use them, double-down on injury reduction and other repair supports.
• Reduce chronic stress; strengthen social ties. Stress chemistry raises blood pressure, glucose, and clotting factors while impairing repair. Kendrick’s top intervention: “Be happy. Don’t worry.” It’s not glib; it’s vascular biology.
  He points to the Roseto community in the U.S., where dense social networks were associated with strikingly low heart disease: “The people who avoid disease and live longest are the people with the strongest social ties. Period.”

The Take-Home

Kendrick’s case doesn’t rest on contrarianism; it rests on coherent physiology. Healthy endothelium is a fortress. When that fortress is breached, the body’s emergency patch is a clot, which is then covered and (usually) remodeled away. Atherosclerosis is what happens when that cycle repeats at the same stressed location and repair is incomplete.

Does LDL participate in the drama? Of course—like every circulating component does when a clot forms. But presence in the debris field isn’t proof of guilt. When you align barrier biology, hemodynamics, histology, and the behavior of risk factors, the initiator is injury, the visible mass is clot remnants, and the progression is repair gone partial.

And that’s actionable. If the disease is injury + clot + imperfect repair, then the antidote is:

• Cause less injury (don’t smoke; avoid glucose spikes and toxins; manage BP; treat infections early);
• Tilt toward smaller clots (cool inflammation; know your Lp(a));
• Repair better (sunlight, movement, nutrient sufficiency, sleep, stress reduction, and—yes—friendship).

The science, it turns out, points to a way of living that’s both mechanistically sane and deeply human. As Kendrick quipped, humor is “a funny way of being serious.” So is this reframing: it takes a familiar story, flips the spotlight to where the biology actually is, and returns control to the simple things we can do every day to keep our vascular “slime coat” intact and our inner “scabs” from ever needing to form.