Role of the Coagulation System in PCa.

[pjoshea13]

New study below.

A key supplement for preventing Mets, IMO, is nattokinase. It dissolves fibrin & reduces fibrinogen levels. It potentially eliminates micro-clots, which are probably essential for metastasis.

I have written a number of posts on the subject. D-dimer can be monitored to ascertain clot status. Elevated levels may indicate active clots. Prudent to assume that is the reason.

The subject doesn't get much press in the U.S., so no surprise that this is a German study.

"Several components of the hemostatic system, including D-dimers, von Willebrand Factor, thrombin, fibrin-/ogen, soluble P-selectin, and prothrombin fragments 1 + 2 were either overexpressed or overactive in genitourinary cancers."

"Hypercoagulation was in general associated with a poorer prognosis. Experimental models and small trials in humans showed reduced cancer progression after treatment with anticoagulants."

"... experimental and clinical evidence suggests procoagulatory activity of genitourinary neoplasms, particularly in prostate, bladder and kidney cancer. This may promote the risk of vascular thrombosis but also metastatic progression. Clinical studies linked elevated biomarkers of hemostasis with poor prognosis in patients with genitourinary cancers. Thus, anticoagulation may have a therapeutic role beyond prevention of thromboembolism."

Although the appeal of nattokinase will perhaps be apparent to those with local disease, I feel that it is valuable when mets are present. No point in allowing the number of mets to increase.

-Patrick

ncbi.nlm.nih.gov/pubmed/288...

Clin Genitourin Cancer. 2017 Jul 26. pii: S1558-7673(17)30210-0. doi: 10.1016/j.clgc.2017.07.013. [Epub ahead of print]

Role of the Coagulation System in Genitourinary Cancers: Review.

John A1, Gorzelanny C2, Bauer AT3, Schneider SW4, Bolenz C5.

Author information

1

Department of Urology, Ulm University Medical Centre, Ulm, Germany; Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Electronic address: [e-mail].

2

Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany; Department of Dermatology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

3

Experimental Dermatology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

4

Department of Dermatology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.

5

Department of Urology, Ulm University Medical Centre, Ulm, Germany.

Abstract

Tumor progression is associated with aberrant hemostasis, and patients with malignant diseases have an elevated risk of developing thrombosis. A crosstalk among the vascular endothelium, components of the coagulation cascade, and cancer cells transforms the intravascular milieu to a prothrombotic, proinflammatory, and cell-adhesive state. We review the existing evidence on activation of the coagulation system and its implication in genitourinary malignancies and discuss the potential therapeutic benefit of antithrombotic agents. A literature review was performed searching the Medline database and the Cochrane Library for original articles and reviews. A second search identified studies reporting on oncological benefit of anticoagulants in genitourinary cancer. An elevated expression of procoagulatory tissue factor on tumor cells and tumor-derived microparticles seems to stimulate cancer development and progression. Several components of the hemostatic system, including D-dimers, von Willebrand Factor, thrombin, fibrin-/ogen, soluble P-selectin, and prothrombin fragments 1 + 2 were either overexpressed or overactive in genitourinary cancers. Hypercoagulation was in general associated with a poorer prognosis. Experimental models and small trials in humans showed reduced cancer progression after treatment with anticoagulants. Main limitations of these studies were heterogeneous experimental methodology, small patient numbers, and a lack of prospective validation. In conclusion, experimental and clinical evidence suggests procoagulatory activity of genitourinary neoplasms, particularly in prostate, bladder and kidney cancer. This may promote the risk of vascular thrombosis but also metastatic progression. Clinical studies linked elevated biomarkers of hemostasis with poor prognosis in patients with genitourinary cancers. Thus, anticoagulation may have a therapeutic role beyond prevention of thromboembolism.

Copyright © 2017 Elsevier Inc. All rights reserved.

KEYWORDS:

Anticoagulants; Blood coagulation; Cancer metastasis; Hemostasis; Urogenital neoplasms

PMID: 28822718 DOI: 10.1016/j.clgc.2017.07.013

[Jayg57]

On the other hand:

"Compared to non-users, warfarin use was associated with an increased risk of PCa [multivariable-adjusted hazard ratio (HR) = 1.11, 95% confidence interval (CI) 1.01-1.22]. This was limited to short-term, low-dose use, and was not observed in long-term use. A similar overall risk increase was observed for Gleason grade 7-10 PCa. Low-dose, short-term use of warfarin was associated with an increased risk of metastatic PCa. However, the increase in risk vanished with continued use. Compared to other anticoagulants, low-dose use of warfarin was associated with a slightly elevated overall PCa risk (HR = 1.19, 95% CI 1.00-1.43). The increase in risk disappeared in long-term, high-dose use.

CONCLUSIONS: This study, which included a larger number of PCa cases with warfarin exposure than previous studies, does not support previous notions of decreased risk of PCa among warfarin users. A similar risk of PCa was found among warfarin users and the general population, and no difference in risk was found between warfarin and other anticoagulants."

Kinnunen PT, Murtola TJ, Talala K, Taari K, Tammela TL, Auvinen A. Warfarin use and prostate cancer risk in the Finnish Randomized Study of Screening for Prostate Cancer. Scand J Urol. 2016;50(6):413-419.

ncbi.nlm.nih.gov/pubmed/?te...

I certainly don't know the answer, just curious. I think alt medicine practitioners are big on nattokinase for cancer.

[pjoshea13 in reply to Jayg57]

Jay,

I have no idea why short-term low-dose warfarin would increase PCa risk. Perhaps there is a clue in the patient profiles.

Numerous papers advise that a man presenting with a DVT be screened for PCa. Coagulation problems may be the first sign of cancer in those who do not test PSA levels regularly. Men with cancer-related clots who start warfarin before PCa is found, will look to a researcher as though warfarin increased PCa risk.

...

I was on warfarin for 3 months & was eager to get off it. An important supplement for me is vitamin K2. Not only for bone density & arterial calcification-related reasons, but also because there is a PCa survival association. The loss of vitamin K while on warfarin is a disaster IMO.

Here is a 2010 article from LEF on "The Remarkable Anticancer Properties of Vitamin K":

lifeextension.com/magazine/...

-Patrick

[Jayg57 in reply to pjoshea13]

20 years ago Judah Folkman talked about platelets sequestering both pro- and antiangiogenic factors which could determine the fate of metastasizing cancer cells.

Maybe warfarin impacts the balance or the release of these opposing factors from platelets, with the alternative effects being time or site dependent.

“5.1. The platelet angiogenesis proteome.

We previously reported that platelets contain both

proangiogenic proteins and antiangiogenic proteins. We

have subsequently found that these angiogenesis regulatory

proteins are in the alpha granules of platelets. Furthermore,

we have found that platelets continuously scavenge angio-

genesis regulatory proteins from the plasma and concentrate

them against a steep gradient. Angiogenesis regulatory

proteins sequestered by platelets are not completely released

into serum during clotting. These results have two imme-

diate practical implications.

It has now become possible to detect microscopic-sized

tumors of about 1 mm3 or less in mice by quantifying the

platelet concentration of a panel of angiogenesis regulators

using mass spectroscopy of platelet lysates or enzyme-linked

immunosorbent assay analysis of these lysates. Although

platelets only live about 4 to 5 days in mice (8 days in

humans), they appear to conserve the angiogenesis proteins

they accumulate so that each subsequent generation of

platelets has a memory of angiogenesis-based proteins that it

has captured from a tiny microscopic tumor. In the future, it

may be possible to use the platelet angiogenesis proteome to

detect recurrent cancer (such as colon cancer or breast

cancer) years before the tumor is symptomatic or can be

visualized by conventional methods. It may then become

possible to treat the platelet angiogenesis proteome as a

biomarker by using relatively nontoxic angiogenesis inhib-

itors until the biomarker falls to normal levels. More recently,

the surprising discovery has been made by Joseph Italiano

that proangiogenic proteins are housed in one set of alpha

granules and antiangiogenic proteins are housed in a

different set of granules. This finding has important

implications for the orchestration of angiogenesis proteins

during early and late stages of wound healing.

The sequestration of angiogenesis proteins into platelets

also explains why the measurement of plasma levels of

angiogenic proteins, such as VEGF, often does not correlate

with severity of cancer. It will become important to measure

these proteins in platelet lysates. In fact, it has recently been

reported that when Avastin is administered to patients it is

taken up by platelets where it binds to VEGF.

Recently, Randolph Watnick in our laboratory has found

that certain primary human tumors secrete into the plasma a

specific protein that suppresses the angiogenesis inhibitor

thrombospondin-1 only in the fibroblasts and endothelial cells

of a specific future site of metastasis. For example, a human

prostate cancer that metastasizes only to lung in mice

“prepares” the future metastatic site by suppressing thrombo-

spondin-1. This facilitates angiogenesis for any tumor cells

arriving at that site, in contrast to any other site, where

thrombospondin-1 would be at its normally high level.

Because different tumors may secrete different “metastatic

site preparation proteins”, these could conceivably be treated

with antibodies (analogous to Avastin) to prevent future

metastasis. The surgical biopsy of a primary tumor may

supply the cells from which the protein can be identified, so

that future metastatic sites will be known perhaps years

in advance.”

Folkman J. Is angiogenesis an organizing principle in biology and medicine?. J Pediatr Surg. 2007;42(1):1-11.

jpedsurg.org/article/S0022-...

[pjoshea13 in reply to pjoshea13]

I posted:

"I have no idea why short-term low-dose warfarin would increase PCa risk."

I think I answered the "short-term" part. If warfarin use is because of cancer-related clots, PCa is more likely to be diagnosed in the short-term. Or, to state it another way, the longer one goes without a PCa diagnosis, the less the likelihood that the clot was PCa-related.

But what about "low-dose"?

The standard approach is high-dose Warfarin for 3 months, 6 months, 9 months or a year. Low-dose has been used after the initial therapy for maintenance, to minimize bleeding risk. But this does not seem to be what the researchers meant.

"Even though there are no convincing data, it is generally preferred that the elderly be started on a low-dose warfarin regimen because of the exaggeration of anticoagulation response in this age group." [1] [2]

i.e. low-dose warfarin from the get-go might indicate an elderly subset, & that could mean a higher rate of PCa detection.

So the association of "short-term low-dose warfarin" with higher detection makes sense.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/158...

[2] ncbi.nlm.nih.gov/pmc/articl...

[Hidden]

the D-dimer test is positive for lots of things. Negative is nice, but positive is problematic.

sensitive but not specific.

medlineplus.gov/ency/articl...

I have to say I agree with you all the same. But rivaoxiban or the other newer drugs probably work better, and with less risk of cerebral hemorage. Is that relevant? I dont know.

[pjoshea13 in reply to Hidden]

Yes, D-dimer can mean other problems, but the probability that it is elevated because of a clot is significantly higher with PCa.

"ISMP Ranks Xarelto Most Dangerous Drug in the United States"

drugnews.net/news/ismp-rank...

Xarelto = Rivaroxaban

-Patrick