Hematocrit drives Blood Viscosity- Does that Matter in Men on TRT? Effect of Altitude?

[tareload]

Hi ExcelMale folks, I wanted to start off by expressing my gratitude for this site, all of the amazing work that has been put in to make this place such a great source of information. I would expect no less from a chemical engineer .

I've been following this "debate" about how to properly manage TRT users and hematocrit levels and am really shocked. I'm not going to link to the videos or podcasts that have surfaced recently in this post directly but the debates corresponding to this concept have been covered here at ExcelMale.

> High T and High red blood count Q​

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> Should We Be Managing Estradiol and Hematocrit in Men on Testosterone Replacement?​

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> Dr Neal Rouzien's Position on Hematocrit and Estradiol Management​

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> New Data On Why Some Men Don’t Need Phlebotomy w/ Dr. John Crisler​

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The community at ExcelMale is very fortunate to have Nelson (a chemical engineer who understand fluid dynamics) and Dr. Saya who has a remarkable mind. His discussion in the above link is spot on.

I actually listened to a recent podcast where the host suggested a Hct level of 55% is optimal, but didn't fully disclose what the objective function was. It's an important clarification: longevity/performance/what? What worries me about the recommendations I've listened to is that some poor fellow is going to use this advice and think an Hct level in the mid 50s is perfectly reasonable and nothing should be done to correct this. Again, depending on this person's objective function (i.e., a competitive athlete) maybe they shouldn't do anything in the short term to maximize athletic performance. But for the vast majority of folks looking for functional longevity and compression of morbidity, the medical literature is quite clear a corrective action should be taken. In this thread I'll share some literature, resources to help inform TRT users and demonstrate that elevated Hct is not benign.

I can't think of a better way to think about this topic that what Dr. Saya states many times that it's about "balance" as you are trying to juggle a host of feedback loops and physiological responses. Don't screw yourself up and think that long term elevation of hematocrit is no big deal. I hope you enjoy the reading material so you can make an informed decision about your health. You are taking a healthy step forward to correct hormonal deficiency so don't then take a step back when it comes to your heart and ignoring elevated Hct.

Here's a recent review article that discusses the vascular remodeling response to increased blood viscosity. The first question you should ask yourself before reading this is: if increased blood viscosity is of no concern then why have mammals evolved to possess this response? More to come...

The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias

The systemic vascular resistance response: a cardiovascular response modulating blood viscosity with implications for primary hypertension and certain anemias


Gregory D. Sloop, Joseph J. Weidman, John A. St. Cyr
First Published June 25, 2015 Review Article
https://doi.org/10.1177/1753944715591450

Abstract
Without an active regulatory feedback loop, increased blood viscosity could lead to a vicious cycle of ischemia, increased erythropoiesis, further increases of blood viscosity, decreased tissue perfusion with worsened ischemia, further increases in red cell mass, etc. We suggest that an increase in blood viscosity is detected by mechanoreceptors in the left ventricle which upregulate expression of cardiac natriuretic peptides and soluble erythropoietin receptor. This response normalizes systemic vascular resistance and blood viscosity at the cost of producing ‘anemia of chronic disease or inflammation’ or ‘hemolytic anemia’ both of which are better described as states of compensated hyperviscosity. Besides its role in disease, this response is also active in the physiologic adaptation to chronic exercise. Malfunction of this response may cause primary hypertension.

 

[tareload]

Nelson has daylighted this qualitatively in a previous post, but here's actual experimental data to help ground yourself on a plot of what Hct concentration vs blood viscosity actual looks like.

This graph is taken from paper whose link is attached. This ain't a commercial but those of you working with Dr. Saya are fortunate. Read this paper if you want to understand why increased hematocrit causes your heart to work harder (see Fig. 2 of pdf link for synopsis):

Blood viscosity is non-linear function of Hct. I cringe when I see videos/posts stating that you actually are just fine in the mid to upper 50s. That’s why those truly informed start talking about protective measures when you start using TRT/AAS to counteract these issues. Some that bear discussion include losartan (ARB), taurine, alpha-lipoic acid, etc. Then there's the even simpler discussion of reducing your T dosage vs phlebotomy.

Do you really want your heart working 20% harder all the time when it’s avoidable. Integrate that work over a significant time span and you start to see potential for early (earlier than it needs to be) heart failure.

Enjoy the reading:
Effect of hematocrit on blood pressure via hyperviscosity

Abstract

Increase in blood viscosity, defined as resistance to flow, is one factor in hypertension and atherosclerosis that contributes to the morbidity and mortality associated with tissue ischemia. In this research we evaluated the effect of hematocrit on increasing viscosity, and possible related changes in blood pressure, flow rate, and the equivalent physiologic compensation ratios. Blood samples were taken from 32 healthy individuals and centrifuged for 5 min at 3000 rpm to obtain 2.5 mL of erythrocyte mass from each. Then, at each step 0.5 mL of plasma was consecutively added in a total of 17 steps. The resultant hematocrit and viscosity changes were measured. Viscosity measurement was performed by capillary viscometer. The results were evaluated by the Student t test. It was observed that in the range of 60.16% and 25.32%, a 10.99% increase of hematocrit produced an increase of 1 unit relative viscosity, which means approximately a 20% increase in blood viscosity for a healthy individual. According to Poiseuille's equation, with a constant vessel length, if viscosity is increased by 20%, the decrease in blood flow rate will be 16.67% (100/120 83.33%; 100 − 83.33 = 16.67%). For the physiologic compensation of 20% increased viscosity, blood pressure increase will be 20% or vasodilation will be 4.66% in radius.

Atherosclerotic and some healthy vessels with little vasodilatory capacities might benefit from treatment modalities to decrease the viscosity by hemodilution.

 

[tareload]

This is another component to the discussion: effect of shear stress on the endothelial surface layer. These mice were transgenically modified to have high hematocrit, not PCV.

Excessive erythrocytosis compromises the blood–endothelium interface in erythropoietin-overexpressing mice

Abstract
Non-technical summary
Elevated systemic haematocrit (Hct) increases cardiovascular risk, such as stroke and myocardial infarction. One possible pathophysiological mechanism could be a disturbance of the blood–endothelium interface. It has been shown that blood interacts with the endothelial surface via a gel-like layer (the ‘glycocalyx’, or ‘endothelial surface layer’– ESL) that modulates various biological processes, including inflammation, permeability and atherosclerosis. However, the consequences of an elevated Hct on the functional properties of this interface are incompletely understood. In a transgenic mouse (tg6) model exhibiting systemic Hct levels of about 0.85 the glycocalyx/ESL was nearly abolished. The corresponding increase in vessel diameter had only minor effects on peripheral flow resistance. This suggests that the pathological effects of elevated Hct may relate more strongly to the biological corollaries of a reduced ESL thickness and alterations of the blood–endothelium interface than to an increased flow resistance.

From the conclusions:

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In summary, our results show that in constitutively high haematocrit in transgenic mice, haemodynamic compensatory mechanisms may redress an increase in TPR that might otherwise accompany erythrocytosis. Hence, impaired haemodynamics is unlikely to play a significant role for the increased cardiovascular and microvascular risk observed in tg6 mice. However, the direct effects of polycythaemia on the blood–endothelium interface reported in this study may have corollaries going beyond merely haemodynamic considerations. Excessive erthrocytosis and the accompanying alterations in the interaction between blood components and the vascular wall may trigger pathophysiological mechanisms that lead to a variety of conditions directly impacting cardiovascular health and disease in humans with excessive erythrocytosis, such as in polcythaemia vera, high-altitude-training athletes, and blood doping. The reduction in tESL in tg6 mice is likely to have an adverse impact on microvascular barrier function in terms of both water and macromolecular permeability. Furthermore, a reduction in tESL, together with a reduced cell-free layer, inevitably brings platelets and leukocytes into close proximity with the vessel wall, which, in essence, undermines the role of the blood–endothelium interface making it a more prothrombogenic surface relative to control conditions. The fact that erthrocytosis may lead to chronic thinning of the ESL by a haemodynamic mechanism (i.e. compressive and spontaneously reversible) provides a novel pathophysiological concept which may have important implications for therapeutic intervention.​

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[tareload]

Elevated haematocrit – when too much of a good thing wreaks havoc on the endothelial surface layer

The convective supply of oxygen through the microcirculation to the tissues is the product of blood flow and oxygen content of the blood and depends on red blood cells (RBCs) in two ways. The RBCs contain the oxygen-binding protein haemoglobin so that the oxygen content is proportional to the concentration of RBCs or haematocrit (Hct). Thus increasing Hct leads to an increase in the capacity for the blood to carry oxygen. However, the rheological properties of the blood depend critically on Hct and the viscosity of the blood increases exponentially with Hct. Since blood flow depends inversely on viscosity, increasing Hct leads to a reduction in blood flow. The balance between these two opposing effects of Hct on oxygen supply leads to the concept of optimal haematocrit at which oxygen supply is maximum, usually near a Hct of about 50% (Birchard, 1997).

What happens when systemic Hct rises substantially above the optimal level? Elevated Hct or polycythaemia results as an adaptive physiological response to sojourn at high altitude. A pathological condition known as polycythaemia vera results from an unwanted overproduction of RBCs and is associated with increased cardiovascular risk. Because of the obvious link between elevated Hct and increased blood viscosity, it is generally thought that the increased cardiovascular risk is due to pathological changes in haemodynamics, often resulting in peripheral ischaemia, which lead to increased total peripheral resistance and arterial blood pressure. In an article in a recent issue of The Journal of Physiology, Richter et al. (2011) suggest that the origin of cardiovascular problems associated with chronically elevated Hct lies rather with interactions between the RBCs and the glycocalyx or endothelial surface layer (ESL).

 

[tareload]

Whoops, forgot to provide a primer to help folks navigate the incorrect terminology that sometimes gets thrown out:

Erythrocytosis

Erythrocytosis is defined as an increase in red blood cell (RBC) mass, usually absolute, and is also associated with an increased hematocrit (HCT) and hemoglobin concentration. Although some use the term polycythemia interchangeably with erythrocytosis, the two are not synonymous. Polycythemia in precise terms refers to an increased number of any hematopoietic cell in blood, be it RBCs, platelets or leukocytes. An increase in RBC number (whether relative to changes in body water or an absolute increase in RBC mass) is more precisely called erythrocythemia, but this term is not in general use and we are currently using the term erythrocytosis instead of polycythemia for an increase in RBCs (relative or absolute). Complicating matters is the term polycythemia vera, which specifically refers to a type of chronic myeloid leukemia that only affects the erythroid lineage or, in other words, a chronic erythroid leukemia.

Sloppy use of the term polycythemia vs erythrocytosis in literature showing danger of elevated hematocrit does not disqualify the validity of the scientific data presented. Unfortunately some folks (non-scientists, laypeople) will get caught up in the slick marketing / logical fallacies in some of these podcasts and be convinced that elevated hematocrit is perfectly fine because PCV is not erythrocytosis. No problem! As has been discussed, clotting isn't the only issue here. It's about extra work on your heart and emerging picture of the effect of shear stress on the endothelium.

 

[TorontoTRT]

My hematocrit went from 45 per trt to 55 currently (5 months in) yet blood pressure has stayed exactly the same. Lower normal end. 100/75. Why?

 

[maxadvance]

My hematocrit went from 45 per trt to 55 currently (5 months in) yet blood pressure has stayed exactly the same. Lower normal end. 100/75. Why?

Everyone is likely different, if your hct went to 57 it may go up dramatically. For someone else 55 might be a trigger level. For me personally My body feels fine under 55, over 55 and it's a different story.

 

[TorontoTRT]

This might sound crazy but the higher the hematocrit the better I feel. It’s also nit affecting my resting heart rate 59-60 beats. Are there any specific red flag symptoms one should feel with elevated hematocrit and hemoglobin? I’ve read all the possible symptoms online but I don’t have any. (Still trying to lower hematocrit though) How do you actually feel over 55?

 

[Dr Justin Saya MD]

Great post readalot!

The non-linear relationship of hematocrit to blood viscosity is lost in the weeds to many (think 10% increase in hematocrit = 20% increase in blood viscosity). An astute researcher will also note that the slope of the blood viscosity curve starts increasing right around the low-mid 50s for hematocrit.

 

[TorontoTRT]

So can high hematocrit cause problems immediately or more so long term if it’s chronically high?

 

[maxadvance]

my resting heartbeat doesn't change either, between 55-60 regardless of hct, and I've had hct as high as 58. BP triggered at 55.

 

[TorontoTRT]

What are the main symptoms you notice once hct is too high?

 

[maxadvance]

What are the main symptoms you notice once hct is too high?

I wrote a thread about it, like I said 57 feels like a world of difference than 55 to me

Evidence Based Symptoms, High Hematocrit Effect on Blood Pressure

 

[TorontoTRT]

Do you guys take nitric boosters to prevent side effects? I take about 8g citruline Malate, 1.5g Agmatine sulphate. I also read that l-dopa which is found naturally in mucuna pruriens, lowers hematocrit. Acetyl l-carnitine is also good to prevent blood clotting.

 

[tareload]

My hematocrit went from 45 per trt to 55 currently (5 months in) yet blood pressure has stayed exactly the same. Lower normal end. 100/75. Why?

Thanks for your question. Look at post #2 with fig. 2. What are the compensatory mechanisms shown in the flow chart after viscosity increases? Either blood pressure increases or ... blood vessels dilate. How much your body is capable of vasodilation is a function of a bunch of stuff including health of your blood vessel lining, age, genes, more complicated stuff.

Why did I mention losartan (Blood pressure drug) above? That's what it does, reduce blood pressure more when your body can't on its own by blockading the renin-angiotensin system (See all of the posts around losartan and hematocrit on this site)! So when you have experienced elevated hematocrit above range (what's your margin of safety?), you've got some decisions to make. Reduce your TRT dosage, give blood (which gets into a whole other topic on iron status), BP medication, other NO manipulation. Losartan has been demonstrated to lower hematocrit but now you are getting into polypharmacy and the tradeoffs associated. See all of the posts here at ExcelMale on losartan. Very few free lunches out there. That brings up another question for folks, anyone seen results with hematocrit reduction using 25-50 mg / day of losartan while on TRT (after reaching some type of pseudo steady-state)?

P.S.: Some additional fun reading I don't see discussed regularly by folks who say clinically relevant hematocrit elevation is no biggie. Nothing to see here, move along.... Can you see what this trend in the paper below has to do with the observations shared by folks in this thread?

Nitric oxide scavenging by red blood cells as a function of hematocrit and oxygenation

Abstract
The reaction rate between nitric oxide and intraerythrocytic hemoglobin plays a major role in nitric oxide bioavailability and modulates homeostatic vascular function. It has previously been demonstrated that the encapsulation of hemoglobin in red blood cells restricts its ability to scavenge nitric oxide. This effect has been attributed to either factors intrinsic to the red blood cell such as a physical membrane barrier or factors external to the red blood cell such as the formation of an unstirred layer around the cell. We have performed measurements of the uptake rate of nitric oxide by red blood cells under oxygenated and deoxygenated conditions at different hematocrit percentages. Our studies include stopped-flow measurements where both the unstirred layer and physical barrier potentially participate, as well as competition experiments where the potential contribution of the unstirred layer is limited. We find that deoxygenated erythrocytes scavenge nitric oxide faster than oxygenated cells and that the rate of nitric oxide scavenging for oxygenated red blood cells increases as the hematocrit is raised from 15% to 50%. Our results 1) confirm the critical biological phenomenon that hemoglobin compartmentalization within the erythrocyte reduces reaction rates with nitric oxide, 2) show that extra-erythocytic diffusional barriers mediate most of this effect, and 3) provide novel evidence that an oxygen-dependent intrinsic property of the red blood cell contributes to this barrier activity, albeit to a lesser extent. These observations may have important physiological implications within the microvasculature and for pathophysiological disruption of nitric oxide homeostasis in diseases.

 

[tareload]

Great post readalot!

The non-linear relationship of hematocrit to blood viscosity is lost in the weeds to many (think 10% increase in hematocrit = 20% increase in blood viscosity). An astute researcher will also note that the slope of the blood viscosity curve starts increasing right around the low-mid 50s for hematocrit.

Thanks Dr. Saya, great observation that's why you are astute. Ok, didn't want to go overboard but it's such an important topic, here goes.

Giving you guys some old school literature when stuff got done right. Think about these guys in the lab in 1933/1953:

THE DETERMINATION OF BLOOD VISCOSITY IN MAN BY A METHOD BASED ON POISEUILLE'S LAW​

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THE APPARENT VISCOSITY OF BLOOD FLOWING IN THE ISOLATED HINDLIMB OF THE DOG, AND ITS VARIATION WITH CORPUSCULAR CONCENTRATION.​

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So the formula that does a very nice job fitting all that pretty data in mammals is referred to as Hatschek's formula (hat tip). That is viscosity is equal to viscosity of plasma divided by the quantity of (1-hematocrit raised to the 1/3 power).

So if you take this formula and manipulate to take the derivative of the viscosity with respect to hematocrit (I'll spare you), you can plot out how quickly the function is increasing (rate aka slope) at any point on the curve of hematocrit vs apparent viscosity:


Here I am using a plasma viscosity (eta zero in equation above) of 1.3 cP. The line in blue is viscosity (goes with the left ordinate) and the orange line is the slope of the blue line (goes with the right ordinate or secondary y-axis). You can see blue line goes up pretty linearly but really starts to take off after about 45-50% hematocrit. So going from 50 to 55% hematocrit doesn't result in the same absolute increase in viscosity as going from 40-45% or 45-50% (it's more!).

So what about that plasma viscosity term since the equation above isn't just dependent on hematocrit. Why all that variability in people's experiences with BP, symptoms and hematocrit?

Why must a practitioner be cautious? When was the last time you had your plasma viscosity measured? I haven't done it . Ah, finally a test I haven't run.

So plasma behaves as a Newtonian fluid but its viscosity is a strong function of the proteins within. Take a look at these papers. Guess what really jacks with plasma viscosity, yep you guessed it, inflammation.

Plasma viscosity: a forgotten variable.​

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Abstract

Evaluation of plasma viscosity has been underutilized in the clinical practice. Plasma viscosity is determined by water-content and macromolecular components. Plasma is a highly concentrated protein solution, therefore weak protein-protein interactions can play a role that is not characterized by electrophoresis. The effect of a protein on plasma viscosity depends on its molecular weight and structure. The less spheroid shape, the higher molecular weight, the higher aggregating capacity, and the higher temperature or pH sensitivity a protein has, the higher plasma viscosity results. Plasma is a Newtonian fluid, its viscosity does not depend on flow characteristics, therefore it is simple to measure, especially in capillary viscosimeters. Its normal value is 1.10-1.30 mPa s at 37 degrees C and independent of age and gender. The measurement has high stability and accuracy, thus little alterations may be pathologically important. Inflammations, tissue injuries resulting in plasma protein changes can increase its value with high sensitivity, though low specificity. It can increase in parallel with erythrocyte sedimentation rate (ESR), but it is not influenced by hematocrit (anemia, polycytemia), or time to analysis. Based on these favorable features, in 1942 plasma viscosity was recommended to substitute ESR. In hyperviscosity syndromes plasma viscosity is better in follow-up than ESR. In rheumatoid arthritis, its sensitivity and specificity are better than that of ESR or C-reactive protein. Plasma fibrinogen concentration and plasma viscosity are elevated in unstable angina pectoris and stroke and their higher values are associated with higher rate of major adverse clinical events. Elevation of plasma viscosity correlates to the progression of coronary and peripheral artery diseases. In conclusion, plasma viscosity should be measured routinely in medical practice.​

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Plasma viscosity in inflammatory bowel disease​

So let's review an instructive example with two guys, Joe and Bill. Joe has a plasma viscosity of 1.3 cP and Bill (who's got some immune issues) has a plasma viscosity of 1.5 cP (could be much worse). They both present with hematocrit of 55%. Let's plot it:

Looking at the graphical construction above, Joe (at a Hct of 55%) has a blood viscosity of 7.2 cP. Bill at same Hct has a blood viscosity of 8.3 cP. Guess where Joe's Hct would have to be to give the same blood viscosity as Bill? Just a little north of 60%! So Bill's blood at 55% Hct is behaving the same way Joe's blood would behave at 60%. An equivalent hematocrit reading in two persons does not necessarily indicate the same blood viscosity. Can you see now why a blanket suggestion that hematocrit levels above reference range are not a big deal is flawed practice? Individual mileage may vary.

But hold on, isn't this example quite extreme. Are you exaggerating for effect readalot?

Well, if you substitute 1.1 and 1.3 cP (the normal range endpoints given in paper provided above) for Joe and Bill's plasma viscosity, you draw the exact same conclusions. Modest (10% variation) in plasma viscosity combined with non-linear relationship of serum viscosity vs. Hct can result in very different serum viscosities for two individual's with the same Hct.

Want even more fun...Here's the plot for Joe, Bill, and their buddy Jay who all have Hct of 55%. Remember, Joe's plasma viscosity is 1.3 cP and Bill's is 1.5 cP. They're jealous of their super stud buddy Jay who has a very low serum viscosity of 1.1 cP. How do they compare? Jay would need a hematocrit of 65% to match Bill's serum viscosity even though Bill and Jay have the same hematocrit of 55%.

 

[jdthoosier]

Is it only the ARBs like Losartan that may be able to lower HCT, or are there other classes of blood pressure meds that might have the same ability?

 

[tareload]

Is it only the ARBs like Losartan that may be able to lower HCT, or are there other classes of blood pressure meds that might have the same ability?

Quite a bit of literature out there on ACE inhibitors and ARBs. ARBs seem to be significantly more effective than CCBs. Google hematocrit ARB or hematocrit ACE inhibitor. You can see much of this literature concerns EPO therapy and treatment for renal failure/transplant.

Erythropoiesis and Blood Pressure Are Regulated via AT1 Receptor by Distinctive Pathways

Angiotensin-converting enzyme inhibition in the treatment of renal transplant erythrocytosis. Clinical experience and observation of mechanism.

 

[Vince Carter]

No mention of Platelets?

No mention of other treatments or more succinctly why TRT guys are the only group of people being drained regularly when other drugs or treatments that result in HCT increases, are not being phlebotomized. Even naturally occuring at high(er) elevations increased RBC/HCT, they're not being drained, either.

Lest we destroy a guys Iron and Ferritin, too, which has it's own consequences.

The point being we're placed in this vicious cycle that isn't being applied to any other group. You make me donate, destroy my ferritin (and Iron), tell me to take supplements and eat liver to replenish iron stores, likely(?) spurs HGB/HCT/RBC production, so you make me donate again, and on and on and on...it's a ridiculous cycle to find yourself trapped in.

 

[tareload]

No mention of Platelets?

No mention of other treatments or more succinctly why TRT guys are the only group of people being drained regularly when other drugs or treatments that result in HCT increases, are not being phlebotomized. Even naturally occuring at high(er) elevations increased RBC/HCT, they're not being drained, either.

Lest we destroy a guys Iron and Ferritin, too, which has it's own consequences.

The point being we're placed in this vicious cycle that isn't being applied to any other group. You make me donate, destroy my ferritin (and Iron), tell me to take supplements and eat liver to replenish iron stores, likely(?) spurs HGB/HCT/RBC production, so you make me donate again, and on and on and on...it's a ridiculous cycle to find yourself trapped in.

1. Platelets: Haven't gotten there yet. And thread so far is about concern of elevated Hct. Most discussions I hear immediately jump to clotting without consideration of how elevated Hct itself is pause for concern. Good to start first with the overlooked basics then add in complexity.

2. Other treatments: guess you missed post #15:

Why did I mention losartan (Blood pressure drug) above? That's what it does, reduce blood pressure more when your body can't on its own by blockading the renin-angiotensin system (See all of the posts around losartan and hematocrit on this site)! So when you have experienced elevated hematocrit above range (what's your margin of safety?), you've got some decisions to make. Reduce your TRT dosage, give blood (which gets into a whole other topic on iron status), BP medication, other NO manipulation. Losartan has been demonstrated to lower hematocrit but now you are getting into polypharmacy and the tradeoffs associated. See all of the posts here at ExcelMale on losartan. Very few free lunches out there. That brings up another question for folks, anyone seen results with hematocrit reduction using 25-50 mg / day of losartan while on TRT (after reaching some type of pseudo steady-state)?

3. You jumped right to draining blood, wow that was fast. Other group that get's drained alot: Read up on hemochromatosis. To address your point, a much more elegant approach to handle Hct is to reduce the dose rather than bloodlet. This is a great segue into hemochromatosis and genetics...