T Nation

Does High Hematocrit Lead to Complications for Men on TRT?

I plan on using this thread to capture comments/discussion on secondary erythrocytosis from TRT (Hct/viscosity) and cardiovascular risk. Alot of my previous comments/question/posts have been spread over a number of other’s threads.

In particular, I’ve seen a number of comments (even interviews with Experts) trying to rationalize running Hct high because there’s plenty of people at high altitude that do just fine with high Hct. Truth is there are a fraction of these folks that suffer significant symptoms and they are a great group to study and see how excess blood viscosity manifests in increased cardiovascular risk:

High Blood Viscosity and Hemoglobin Concentration Contribute to Reduced Flow-Mediated Dilation in High-Altitude Excessive Erythrocytosis

Abstract

Excessive erythrocytosis (EE; hemoglobin concentration [Hb] ≥21 g/dL in adult males) is associated with increased cardiovascular risk in highlander Andeans. We sought to quantify shear stress and assess endothelial function via flow-mediated dilation (FMD) in male Andeans with and without EE. We hypothesized that FMD would be impaired in Andeans with EE after accounting for shear stress and that FMD would improve after isovolemic hemodilution. Brachial artery shear stress and FMD were assessed in 23 male Andeans without EE (age: 40±15 years [mean±SD]; Hb<21 g/dL) and 19 male Andeans with EE (age: 43±14 years; Hb≥21 g/dL) in Cerro de Pasco, Peru (4330 m). Shear stress was quantified from Duplex ultrasound measures of shear rate and blood viscosity. In a subset of participants (n=8), FMD was performed before and after isovolemic hemodilution with blood volume replaced by an equal volume of human serum albumin. Blood viscosity and Hb were 48% and 23% higher (both P <0.001) and FMD was 28% lower after adjusting for the shear stress stimulus ( P =0.013) in Andeans with EE compared to those without. FMD was inversely correlated with blood viscosity ( r 2=0.303; P<0.001) and Hb ( r 2=0.230; P =0.001). Isovolemic hemodilution decreased blood viscosity by 30±10% and Hb by 14±5% (both P <0.001) and improved shear stress stimulus-adjusted FMD from 2.7±1.9% to 4.3±1.9% ( P =0.022). Hyperviscosity, high Hb, or both, actively contribute to acutely reversible impairments in FMD in EE, suggesting that this plays a pathogenic role in the increased cardiovascular risk.

Take a look at these plots from the study:

Refresher on FMD:

Flow-mediated dilation

Now couple this information with my previous post on the same Hct values giving very different blood viscosity:

Remember this plot:
image

From the paper’s discussion:

Blood viscosity elicits opposing resistive and shear stress-associated vasodilatory effects on hemodynamics.51,52 Modest increases in blood viscosity have been shown to reduce blood pressure via increased shear stress-associated NO formation but increasing viscosity >50% increased blood pressure.52 Moderate polycythemia may be associated with greater FMD in hypoxemic patients.53 However, the relationship between blood viscosity and Hb becomes steeper in Andeans with EE (Figure 1). Although the mechanisms that determine this relationship remain to be established (see below), endothelial dysfunction in instances of high levels of blood viscosity and Hb may render individuals especially susceptible to increased cardiovascular risk as both whole blood viscosity54,55 and reduced FMD56,57 predict cardiovascular risk and events.

Enlarged brachial artery diameters have previously been reported in participants with EE,10 which appears to be a phenotypic characteristic of this maladaptive response to chronic hypoxemia. The large diameter may be the result of structural adaptations in response to high blood viscosity-associated shear stress, the so-called shear stress normalization hypothesis.58,59 Additionally, there may be a role for chronic hypoxemia in maintaining the conduit artery in a vasodilated state, supported by the observation that oxygen supplementation decreases brachial artery diameter in patients with CMS.10 Thus, enlarged conduit artery diameter is a fundamental component of EE pathophysiology. In non-EE populations, an inverse relationship between baseline diameter and FMD has been observed.60 This has been interpreted to suggest that the same endothelial function is reflected by a progressively smaller percent and absolute FMD response as baseline artery dimensions increase.60 However, FMD increased with hemodilution while baseline artery diameter did not change, providing support that the larger baseline diameters per se do not explain the impaired FMD in EE.

We have identified a role for high Hb and blood viscosity in contributing to the reduced FMD in Andeans with EE. However, the mechanisms responsible for the low FMD in Andeans with EE are likely multifaceted and cannot be completely elucidated from the present study. For instance, increased systemic free radical formation has been reported in Andeans with EE compared to Andeans without,8,12 and this likely contributes to the lower FMD by chronically inactivating NO (oxidative-nitrosative stress).8,50 Additionally, cell-free Hb is a 1000-fold more potent NO scavenger[61–64](https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.119.12780#R61 R62 R63 R64) than red blood cell Hb and can impair endothelium-dependent vasodilation.61,65 Polycythemic patients at sea level have elevated levels of cell-free Hb compared to healthy control participants, and polycythemic patients with hypertension have higher cell-free Hb compared to normotensive polycythemic patients.66 Thus, cell-free Hb may play a role in the NO scavenging and subsequent reduced FMD and increased cardiovascular risk in Andeans with EE.1 Further, measures of erythropoietin to soluble erythropoietin receptor (an erythropoietin antagonist) ratio may have provided additional mechanistic insight, as this ratio is increased in CMS67,68 and erythropoietin has been shown to impair endothelial function in humans.69 Therefore, future investigations should investigate markers of oxidative stress, NO bioavailability (in both plasma and red blood cell), cell-free Hb, and levels of erythropoietin to better dissect the mechanisms linking EE with reduced FMD and related adverse vascular outcomes.

So if you’ve got autoimmune issues, high cRP, elevated plasma viscosity, probably a good idea not to run your Hct up too high! Also, there’s no magic cutoff at a Hb of 21 g/dL. The plot of FMD vs blood viscosity is continuous and shows why cautious providers don’t want to run Hct above 50-51%.

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Ever “feel” better after a double red donation?

Hot off the press:

Acute reductions in hematocrit increase flow‐mediated dilation independent of resting nitric oxide bioavailability in humans

Abstract

Key points

  • Changes in hematocrit influence nitric oxide signalling through alterations in shear stress stimuli and hemoglobin scavenging of nitric oxide; these two regulatory factors have not been assessed simultaneously
  • Isovolumic hemodilution led to a marked increase in brachial artery flow‐mediated dilation in humans
  • The increase in flow‐mediated dilation occurred in the face of an unaltered shear stress stimulus for vasodilation and reduced resting steady‐state nitric oxide levels in the blood
  • Collectively, our data point towards hemoglobin scavenging of nitric oxide as a key regulatory factor of brachial flow‐mediated dilation and highlight the importance of simultaneous consideration of nitric oxide production and inactivation when investigating vascular function in humans

Abstract

Hemoglobin (Hb) may impact the transduction of endothelium‐dependent and nitric oxide (NO) mediated vasodilator activity, given its contribution to shear stress stimuli and diverse biochemical reactions with NO. We hypothesized that an acute reduction in [Hb] and hematocrit (Hct) would increase brachial artery flow‐mediated dilation (FMD). In eleven healthy males (28 ± 7 years; 23 ± 2 kg m−2), FMD (Duplex ultrasound), arterial blood gases, Hct and [Hb], blood viscosity, and NO metabolites (ozone‐based chemiluminescence) were measured before and after isovolumic hemodilution, where ∼20% of whole blood was removed and replaced with 5% human serum albumin. Hemodilution reduced Hct by 18 ± 2% ( P < 0.001) and whole blood viscosity by 22 ± 5% ( P < 0.001). Plasma nitrite (P = 0.01), S ‐nitrosothiols (P = 0.03), and total red blood cell NO (P = 0.001) were collectively reduced by ∼15–40%. Brachial artery FMD increased by ∼160% from 3.8 ± 2.1 to 9.7 ± 4.5% (P = 0.004). Statistical covariation for the shear stress stimulus did not alter FMD, indicating that the increase in FMD was not directly related to alterations in whole blood viscosity and the shear stimulus. Collectively, these findings indicate that hemoglobin scavenging of NO appears to be an important factor in the regulation of FMD under normal conditions through constraint of endothelium‐dependent NO‐mediated vasodilation in healthy humans.

Nice to see you over here.

Thanks very much. I appreciate you having sympathy for my lonely thread. Honored.

Having anything to do with your circulatory system chronically elevated is probably not a good idea. From my understanding, athletes that blood dope do it for temporary effects. Also from my understanding, it’s generally harmless on a blast of testosterone, but you want to keep it in range most of the time. Of course there are case studies of people that had issues from acutely elevated levels, but I think most of those people had an underlying condition of some sort.

Either way there are always risks involved and the best we can do is be educated enough to be smart about what we put into our bodies.

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I posted some similar information over at another forum. Here’s was a response:

None of this matters. Testosterone INCREASES NO production and dilates blood vessels to account for any blood thickening essentially cancelling out any negative side effects. Hence no one on TRT us dropping dead. If this was not true, one would see an increase in blood pressure and heart rate due to thicker blood. From my personal experience over the years my vitals have not changed. Rating heart rate 59 bpm. Blood pressure 100/65. Hematocrit around 52-54. As high as 58.

Read the testosterone impact on Nitric oxide production. If high hct was bad for guys on trt imagine how many guys would drop dead? I agree most people can react differently but the testosterone pharmacology is the same in everyone.

Want to share the same information I shared over there in my response. Happy to think about/entertain any critique/errors in my presentation. My intent is to learn and provide forum for educated discussion.

Thank you.

My summarized response:

You’ve got some false dilemma and circular reasoning fallacy going on here.

So with this logic, there’s no concern with competing effects since testosterone increases NO production, end of story. You can run your Hct as high as you want with impunity since testosterone will increase NO production. So why is it some men see a >20-30 point increase in systolic BP with their Hct rising from 45 to 54% on TRT? Everyone has your cardiovascular response to TRT?

If raising Hct with TRT is bad for guys, then we’d be seeing them dropping dead. So if we don’t observe them “dropping dead”, then no problem with elevated Hct.

Interesting.

Watch from 46:30 till the end:
Testosterone and Estrogen in Men: Good, Bad or Indifferent?

As Dr. Rouzier mentions, men observed at high alititude suffering (i.i., side effects) from excessive erythrocytosis (EE) already have significantly higher testosterone levels than those that don’t have EE. He uses this to justify TRT induced erythrocytosis since it’s testosterone mediated and these guys aren’t “dropping dead”.

Your claim is that use of exogenous testosterone should cancel out any and all increase in viscosity due to increased Hct from the testosterone? So should we give these guys with EE at high altitude more testosterone? They must not be making enough. They need more? Or is it that they need exogenous testosterone since their endogenous testosterone (which is already high compared to control population) is not high enough?

Take a read:
High serum testosterone levels are associated with excessive erythrocytosis of chronic mountain sickness in men

I’ve read over and over the claim that people at altitude have high Hct and they are fine. They aren’t “dropping dead”. Therefore, guys with high Hct from TRT are fine. I took the time to post some recent mechanistic study of why running Hct up too high can be problematic and posted before why all Hct values are not created equal (marked variation in blood viscosity vs Hct depending on plasma viscosity status).

So if you don’t want to read, that’s up to you. But for others trying to make sense of all this, the concern I am trying to daylight is not an acute event, “dropping dead”, or even clotting issue leading to stroke. It’s long term wear and tear on the heart leading to early failure. When you die prematurely from heart failure there may be no one there pointing out “see, he ran his Hct too high for 10 years.”

I summed this up in a thread on another forum (edited for length):

The primary concern with elevated blood viscosity is hypertension, increased shear stress to the lumen (I’m sure you are familiar with what that does), and risk of ischemia and reduced perfusion for compromised patients / older patients. Also, what’s the concern with young person running high blood viscosity for years? Ask AAS abusers what the long term implications of elevated Hct are? Integrate out over 20 years the cost of making your heart do extra, measurably more work. Combine that with a patient who has limited vasodilation ability.

So according to this logic, no worries with elevating serum viscosity, just let it ride? For a patient with plenty of mileage on the heart, pre-CHF or CHF, no worries with cranking up the blood viscosity? Harmless?

This response is lazy and avoids having to discuss the fact the heart is a pump and a pump is designed to operate on a pump curve (just to keep it simple). Depending on the viscosity of the fluid the pump is pumping, you will land on a point on that curve. Surely you understand the long term implications of running a pump too high on the gpm vs hp curve? Any concerns for long term issues if you want that pump in service for a while? We aint talking about a pump in a manufacturing facility that can be replaced rather easily. We are talking about a heart.

image

For folks who talk about optimization, you seem to not understand or ignore the penalty function associated with performance vs longevity. For readers, I’ve shared what I think is important for you to consider. Take care of your cardiovascular system. That means use reasonable caution. Running your Hct above 50, or even 55 is not that. But given the TT levels you guys are recommending, I can see how this little inconvenience causes an issue. Elevated Hct has to be harmless in your practice otherwise you have to have your patients doing an oil drain on a regular, painful basis.

Further thoughts in response to above copied hear to stimulate discussion/review/thoughts/feedback:

@_____, help me understand how TRT would fundamentally shift the qualitative shape of the curves attached below? In order for testosterone to counteract any and all increase in blood viscosity via increased hematocrit, it would have to remove inflection point below on the plots of peak NO vs hematocrit:

The Effect of Small Changes in Hematocrit on Nitric Oxide Transport in Arterioles

Figures 9 and and 10 explore this behavior in detail. Figure 9 shows the relationship between peak CNO and systemic Hct for several values of the exponent m in the constitutive equation [24]. For m = 5 used in the simulations presented in Figure 8 (and other values of m as small as 2), the CNO -Hct relationship exhibits an inflection point, at which CNO reaches its maximum and then starts to decrease. This is due to the asymptotic behavior of RNO ,max (see the constitutive equation [24] and/or Figure 3a). In this limit, further increases in shear stress (and Hct) do not affect NO production and the increased consumption of NO by RBCs is no longer compensated by increasing shear-induced NO production, thus causing NO availability to decrease beyond the inflection point. The exponent m in the constitutive equation [24] determines its steepness and, hence, the rate at which NO production varies with shear stress. Larger values of the parameter m correspond to a steeper increase in NO production with shear stress and, hence, to a sharper increase in NO availability with rising Hct. Figure 10 confirms that this behavior remains essentially the same for different values of the glycocalyx thickness (in these simulations we set m = 5).

The following mechanisms combine to produce the nonlinear relationship between CNO and Hct.

  1. The rate of NO consumption by the RBC core increases with Hct.
  2. Blood viscosity and shear stress at the vessel wall increase with Hct.
  3. O2 availability and NO production rates increase with Hct (equation [7]).
  4. The thickness of the plasma layer decreases and shear stress increases with Hct (equation [16]).
  5. The distance NO must diffuse before being consumed by RBCs in the core decreases with Hct.

Effects 2, 3, and 4 cause NO availability to increase, whereas effects 1 and 5 have the opposite effect. Interaction of these competing effects results in the behavior shown in Figures 9 and and10.10. It is worthwhile emphasizing that changes in the relative strengths of any of these phenomena may have quantitative and qualitative effects on the final relationship between NO availability in the vascular wall and systemic Hct.

Thanks for your share and thoughts. I appreciate your humility in approaching this and your realization that there’s a fair amount of uncertainty that needs to be considered. We need more of this type of approach as opposed to a blanket statement such as TRT induced erythrocytosis is harmless.

So with the competing effects of NO increase (lowering pumping burden on the heart), and HCT increase (increasing the pumping burden on the heart), would heart rate and BP be good indicators if high HCT is a risk?

For example, maybe HCT is 54, but BP is 120/90 and HR is 60 at rest. Does this person have a significant risk of heart issues because HCT is high?

In another thread I started on here (which did not get much attention), I asked this question. My reasoning on this, was if HCT was really bad, it should show in HR and BP. From a mechanical standpoint, a pump is working harder and wearing more when pressure increases and rate of pumping increases.

Is that over simplified? Is there something else about HCT being high that causes damage over time?

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For a second there I thought I had not “liked” your comment about this on the thread you started:

But then I breathed a sigh of relief that I had. I think that’s a fantastic initial screening tool and simple as many elegant tools are. Great point.

My blood viscosity and your blood viscosity at the same hematocrit (e.g., 54%) may be very different as I tried to show in a previous post. My concern is some guy watches Dr. Rouzier’s videos and has a BP of 150/90 with RHR of 85 and rationalizes it away. There are providers that have posted on here that categorically dismiss the concept of secondary erythrocytosis due to TRT being potentially problematic (especially long term).

Thanks for adding this.

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I had forgotten if you responded to my thread TBH. My last hct was 47, HR is low typically (55ish), BP has been just a bit over range, but I suspect losing 20 lbs has bought it down. I am going to buy a bp monitor, just so I get more frequent measurements.

The other element of this is duration time, which should be daylighted. How long can you run a good BP/RHR with an elevated Hct? A patient should be monitored for drift over time as they age (NO production capacity may drop/aging). Actually Dr. Justin Saya has described this really nicely over at that other forum I can’t link to using clear language which leaves the element of uncertainty open. I hope he won’t mind me sharing it here and full atttribution given below:

Justin Saya, MD
May 10, 2017

QUOTE
There are valid points on both sides of this.

Fact: polycythemia vera and erythrocytosis are COMPLETELY different phenomena and should not be confused (though the terms are often erroneously used interchangeably). Polycythemia vera is without a doubt MORE risky, but that doesn’t mean erythrocytosis comes without (longterm) risk.

Fact: though the physiology is similar, erythrocytosis from TRT is NOT a physiologic erythrocytosis, but is IATROGENIC. Though physiologically similar, the ethics and medico-legal considerations are certainly much different.

Fact: there is no solid data of increased risk of MI, DVT, etc that is attributable directly to appropriate TRT (I know we all agree on this one).

My take: as I’ve said before, it is not concern for MI, DVT that presents itself to me with TRT-induced erythrocytosis, but more the LONGTERM vascular consequences. To be clear, I’m generally referring to HCT >53 which is about where I draw the line LONGTERM. Most folks at high altitude DO in fact have higher H/H than their counterparts at sea level, however most are NOT HCT > 53 unless they have multiple exacerbating factors contributing (smoker, high iron levels/intake, OSA - this is a BIG one, COPD, + TRT). We all agree higher HCT = more viscous blood. If we look at simple fluid dynamics and the laws of physics, thicker fluid (blood) inside of a pipe (vessel) = higher pressure (blood pressure). I’ve seen this countless times in patients requiring blood donation or therapeutic phlebotomy – BP drops, sometimes dramatically, afterwards and generally remains at the lower levels until (if/when) HCT rises again.

Now of course we also have the other end of the equation with enhanced nitric oxide production - which helps as it dilates the pipe (vessel) - consequently counterbalancing the increase in pressure. The problem is that this vasodilation from nitric oxide is VARIABLE over time, whereas the increased HCT is more constant…meaning that this teeter-totter of “thicker blood” counterbalanced by nitric oxide vasodilation, will certainly present times when the viscosity side of the equation is at a distinct advantage. Thinking of it another way, the body is able to adapt REMARKABLY to many differing situations (one of which noted above with the vasodilation), but nonetheless has it’s functional limits. Think of it as an airplane that flies at 60-70% of its functional engine capacity (just estimates as I’m not a pilot!) - this piece of machinery has the capacity to utilize a higher percentage of its capacity, but keeping the “normal operating capacity” of the plain at 60-70% gives that added safety margin. The plain can then “throw it into overdrive” and utilize a higher percentage (temporarily) of its capacity when the situation calls for it. This is a crude analogy, but hopefully will make some sense. For the human side - the human body has a capacity to TOLERATE (probably the best term) HCT levels very high under certain situations as an adaptive mechanism, but the higher the HCT goes you are eating into that safety margin for the max capacity of the cardiovascular system and thus reduce the ability of the cardiovascular to remain plastic and adaptable to other changing conditions or insults. For instance, all may be well when the “teeter-totter” of viscosity/nitric oxide is all balanced, but what about when the patient experiences times of reduced nitric oxide production (or other reasons that the pipe won’t dilate…like atherosclerosis as they age)…well then the equation is shifted squarely in favor of the higher viscosity = higher BP --> increased shear forces on arterial walls --> increased risk of macro and microvascular pathology, etc.

We don’t have longterm data (and likely will not for a long time to come) for MANY of the interesting and debatable talking points related to TRT and other hormonal treatments. We can just weigh the current data we have, use our own clinical judgment and understanding of the physiology of the human body, and sprinkle in a little common sense from time to time to make the decisions we feel are in the best interest of our patients longterm.

I personally would not feel forthright in telling one of my 30-40-50 year old patients that sustaining an iatrogenic erythrocytosis with HCT >53 for the next two, three, or four decades of their life will not present any longterm risk…but it’s a debatable topic and one for which each provider (and patient) must determine where they stand and approach it accordingly.

The latest articles I posted up above help to further reinforce these concepts; the body doesn’t have an unlimited capacity via NO production to bail out any and all Hct increase. There seems to be a huge variation in man’s dose response to given unit of TRT. Even without JAK2 mutation, some guys aren’t blessed with good Hct response to even modest exogenous TRT dosage.

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Another piece to this would be endothelial dysfunction over time caused/correlated by increased shear stress on the lumen. This may also be a considerable factor in the loss of NO production over time.

Hemodynamic shear stress and the endothelium in cardiovascular pathophysiology

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@yeti308 @dbossa, here’s another thread dedicated directly to the Hct hand waving. Feel free to use/discuss in your group. Scott may be interested in the latest studies I review above.

Hi Danny, thanks for taking the time to provide this feedback. Let’s keep the correspondence anonymous (reviewer and reviewee) that way we can all focus on the science without any concerns of ego/reputation, etc.

Point on Hct vs viscosity is well taken that’s why I went to the trouble of doing this whole analysis:

image

All Hct is not created equal when it comes to blood viscosity. Completely agree it’s not black or white hence trying to increase the understanding and dialogue about high Hct, especially for men with autoimmune, high cRP, other inflammation issues where their plasma viscosity is elevated and whole blood viscosity is a strong f(Hct+plasma viscosity).

Look forward to any in depth review/discussion you get from others. All of this would make a great video with the right folks who understand the math/physics and biology. And this Doctor is correct, we need studies on men doing TRT.

Curious if any of the providers in your network have ever utilitized this test or one like it:

Any high elevation guys on TRT in here? If there is, what is your average HCT? The majority of guys with symptoms of high HCT are not hydrating enough, and some simply have other issues along with the rare cases of a very specific syndrome. But the real question is why arent guys who live at higher elevations on TRT not dropping dead?
The answer is always going to be compensation. The body really does know what to do, and for the rare cases, intervention is perhaps the only way.

I have forwarded your replies.

A reply from anon doc:

Can you find out if he has the details on the test? I can’t find it on there. To know HOW they’re measuring viscosity here? I like that this guy seems very reasonable.

My main issues are philosophical. How do we know the “viscosity” being measured here is relevant? Many of these use assumptions based on "laws for fluids in tubes, that have been shown not to really apply to complex human vasculature, etc. These are always the issues with “tests” (as we know with ‘covid’, LOL). Does the test MEAN anything? Have they been validated? Etc, etc.

My apologies on not replying to this. There’s a vast literature out there of validating human blood viscosity:

First part in multi-part series…

Part 3:

Some of the original work on developing a predictive formula:
https://www.ahajournals.org/doi/pdf/10.1161/01.CIR.81.1.107

I’ve probably been too optimistic trying to cover this type of very complex subject matter in a forum. I appreciate you sharing my response to the Doc and his response back.

Here’s some additional interesting reading suggesting running your WBV up is probably not a great plan (again correlation, not causation proved).

image

@middleages, maybe you will find this of interest. My hypothesis is that hyperviscosity won’t result in an easily quantifiable or detectable acute event, but it’s cumulative effect over time may be significant. Men affected won’t drop dead, but slowly recline (at least that’s my hypothesis).

Feel free to seek the opinion of your trusted hematologist and vascular surgeon.

Talk down to people much? There are people here who understand what you’re saying just fine. I usually like seeing what you have to say