Thromboxane & Aspirin

[pca2004]

New British study below [1].

"Pre-clinical models demonstrate that platelet activation is involved in the spread of malignancy."

(Metastasis is dependent on unwanted coagulation. This is why I use nattokinase to dissolve unwanted clots, and the D-dimer test to ensure that there are no active clots.)

It is well-known that low-dose aspirin can inhibit platelet aggregation - a necessary step for clot formation.

"Urinary 11-dehydro-thromboxane B2 (U-TXM), a biomarker of in vivo platelet activation ..."

Actually, thromboxane A2 triggers platelet activation. Thromboxane A2 is the precursor of thromboxane B2. Urinary thromboxane B2 can therefore be viewed as a surrogate for platelet activation.

Thromboxane ("thrombo" as in thrombosis) in cancer is a result of chronic nuclear factor-kappaB [NFkB] activation. One of the many proteins produced is COX-1, which acts on the omega-6 fatty acid arachidonic acid to generate thromboxane A2. Aspirin is a cox-1 inhibitor.

"716 patients (breast 260, colorectal 192, gastro-oesophageal 53, prostate 211) median age 61 years, 50% male were studied. Baseline median U-TXM were breast 782; colorectal 1060; gastro-oesophageal 1675 and prostate 826 pg/mg creatinine; higher than healthy individuals (~500 pg/mg creatinine)."

"Aspirin 100 mg daily decreased U-TXM similarly across all tumour types (median reductions: 77-82%)."

As expected, "Aspirin 300 mg daily provided no additional suppression of U-TXM compared with 100 mg."

"Thromboxane biosynthesis should be explored further as a biomarker of active malignancy and may identify patients likely to benefit from aspirin."

Aspirin, even at the low dose, is not without problems (would the FDA approve it today?). Following the aggregation of platelets, there begins the accumulation of fibrin to form the clot. I rely on nattokinase (to dissolve the fibrin) - and D-dimer testing - to deal with on-going clotting. Aspirin can be harsh on the stomach & kidneys. Aspirin users should periodically check D-dimer too.

***

From the old century, a Swedish study [2].

"Oestrogen has been proposed to influence platelet activity and formation of the vasoactive eicosanoids thromboxane and prostacyclin."

"Ten consecutive male patients with prostatic carcinoma participating in a randomized study comparing the effects of parenteral oestrogen therapy (n = 5) with orchidectomy (n = 5) were included. Oestrogen was given as polyestradiol phosphate 240 mg i.m. every month ..."

"We found a consistent decrease of in vivo formation of thromboxane by approximately 40% during parenteral oestrogen therapy ... and a doubling after surgical castration."

"In conclusion, oestrogen induced a marked decrease of in vivo formation of thromboxane and a marked increase in the ratio of prostacyclin to thromboxane formation in all patients. According to current knowledge this should be beneficial for the cardiovascular system."

The final study, from last year, looked at mortality in African-American men. [3]

"Thromboxane A2 (TXA2) is a platelet- and cyclooxygenase-derived eicosanoid that has been linked to metastasis."

"We measured urinary 11-dehydrothromboxane B2 (TXB2), a stable metabolite of TXA2"

"Urinary TXB2 was inversely associated with aspirin use."

"High TXB2 was positively associated with metastatic prostate cancer (OR = 2.60 ...)"

"Furthermore, high TXB2 was also associated with all-cause (adjusted hazard ratio = 1.59 ...) and prostate cancer-specific mortality (hazard ratio = 4.74 ...)"

-Patrick

[1] pubmed.ncbi.nlm.nih.gov/374...

[2] pubmed.ncbi.nlm.nih.gov/901...

[3] pubmed.ncbi.nlm.nih.gov/342...

[MateoBeach]

Thanks Patrick. Answers at least partially a question I have on whether there is additional anti inflammatory effects for aspirin at doses above the platelet inhibiting dose (81-100mg). This aspects says no, no added benefit at 300mg.

Do you use streptokinase in combination with nattokinase? Paul

[pca2004 in reply to MateoBeach]

Hi Paul,

There is no additional thromboxane reduction with a higher dose - so no additional inhibition of metastasis IMO. Whether there is other dose-related benefit, I don't know.

I'm not sure there is wide appreciation of PCa statistics. With 97% 5-year survival for all stages, it's clear that most will never develop mets. The 5-year survival for localized disease is >99%. Most of the <3% who die within 5 years are 68% of those with distant PCa. We are in a fairly exclusive club! There are 3,100,000 men alive in the U.S. with a PCa diagnosis. Quite extraordinary. But huge turnover in the mPCa community. Aspirin use should target those in that group & those at risk for membership.

Rather than suggesting that all men with PCa take a low-dose daily aspirin, I think that those with high-risk disease should consider it, but the majority should monitor D-dimer. With increased D-dimer activity, nattokinase could speed-up elimination of the clot(s) & low-dose aspirin might be considered.

I'm aware of warnings that elevated D-dimer may not be due to plasmin breaking down a clot, but my number has always been in the lowest range or on the border.

IMO, even men with widespread mets should take steps to avoid additional mets. Although it may seem like closing the barn door too late.

Some men might be drawn to aspirin for cardiovascular reasons, but the last studies I read found benefit only for those who have had cardio events. If the concern is blood clots, a D-dimer test is less invasive and nattokinase seems to be very safe compared to aspirin.

I don't use streptokinase, or anything else, with nattokinase. I rely on the D-dimer test. Unfortunately, the LabCorp test does not report zero, but I'm OK with that.

-Patrick

[MateoBeach in reply to pca2004]

thanks for your thoughts as always. I had coronary EBT calcium score in 900s in my 40s. High BP and LDL. Threw a tiny plaque to my retina at 45. So have been on maximal dose of atorvastatin ever since, baby ASA and BP controlled. No events since (28 years) so presume plaques are stable. Now added nattokinase with streptokinase thanks to you and others.

BTW fairly decent evidence for doxazosin (and prazosin) retarding PC progression and even metastasis. So any advanced PC with high BP requiring medication should consider these. I take doxazosin 2mg BID. Better pharmacodynamics.

[GreenStreet]

Thanks very much. Following our discussions I also use Natto. I also take 75mg aspirin every three days. Does this study encourage you to take more aspirin say 75mg every other day or do you think the potential dangers outweigh the benefits?

[PCaWarrior in reply to GreenStreet]

My MO advised me to take 81 mg every night. I take it 4-5 days a week.

I don't know if the recommendation was specifically for PCa, I use a modified BAT program and aspirin might reduce cardiac risk (unproven as long as you measure hematocrit and act appropriately based on the level).

[Medline]

PCa increases serum TXA2 levels, and ADT further increases these levels.

frontiersin.org/articles/10...

[PhilipSZacarias]

This is excellent post and commentary Patrick. I am writing a paper on the safety of transdermal E2 and you have just provided another paper on the benefits of E2. Many thanks. Cheers, Phil

[hansjd]

Hi Patrick

Help, I'm confused. I thought an omega 3 supplement was a good idea but reading this article it seems that it isn't, as "Thromboxane ("thrombo" as in thrombosis) in cancer is a result of chronic nuclear factor-kappaB [NFkB] activation. One of the many proteins produced is COX-1, which acts on the omega-3 fatty acid arachidonic acid to generate thromboxane A2" which "triggers platelet activation". Can you please clarify this for us? Is it a good idea to take it or not? Thanks

[pca2004 in reply to hansjd]

Oops! Should be 'acts on the omega-6 fatty acid arachidonic acid'

Thanks for spotting that!

Best, -Patrick

[Nfler in reply to pca2004]

Does this include fish oil as the omega 6, that are ok to take as I do 100 mg of aspirin daily along w1200 mg of fish oil…?

[pca2004 in reply to Nfler]

I mis-identified arachidonic acid [AA] as an omega-3 - it is an omega-6.

AA accumulates in PCa lipid rafts. However, EPA & DHA (marine omega-3s) competes with AA & lowers the inflammation potential of the cell.

-Patrick

[Nfler]

ok great thank you, I’ll keep u the fish oil along w aspirin…