Cancer - Inflammation - Hypercoagulation - Metastasis

I was about to post a new meta-analysis of aspirin & metastasis/mortality, when I realized that it needed a preamble covering inflammation, hypercoagulation & metastasis.

The subject of cancer & altered coagulation goes back to before I was born.  The Abstract of a 2000 Dutch paper [1] hits the main points:

a)  "Coagulation disorders occur often in cancer patients."

b)  "Thrombosis or embolism may be the first sign of an underlying malignancy."

c)  "subclinical coagulation disturbances have been found in the blood of cancer patients, for example elevated concentrations of tissue factor or thrombin-antithrombin complexes.

d)  "In 20% of the patients thrombocytosis occurs"

e)  "The role of an activated coagulation cascade in tumour growth is not completely clear, but there is strong evidence that the formation of a temporary fibrin matrix stimulates the formation of new blood vessels (angiogenesis) and supports tumour growth and metastasis formation."

f)  "Preclinical investigations demonstrated that tumour growth and metastasis formation can be inhibited by anticoagulants. Clinical studies suggest a beneficial effect of anticoagulants on the survival of cancer patients"

My take on the paper is that, given what had then been known for quite a while, wasn't it now time to do something about it?  But doctors only use anticoagulants to treat thrombotic events.  There is no interest in treating "subclinical coagulation disturbances" that might facilitate metastasis.  When a man is diagnosed with PCa, does the subject of dysfunctional coagulation ever come up?

I used to be perplexed that coagulation factors become altered at an early stage in cancer - much earlier than metastasis.  Cancer isn't supposed to be be prescient.  How could a tumor 'know' that future metastasis might depend on hypercoagulation?  A clue, for me, was discovering that elevated fibrinogen is a marker of inflammation.  Fibrinogen is turned into fibrin (by the action of thrombin) when a clot is being formed.  Looked as though inflammation creates a procoagulative state.

In a paper [2] to be published in May ["Tissue factor as a link between inflammation and coagulation"]: 

"Due to its receptor activity for factor VII, tissue factor (TF) is primary initiator of the blood coagulation cascade and ensures rapid hemostasis in case of organ damage. Inflammatory cytokines, such as tumor necrosis factor-α or interleukins, strongly induce expression of both full-length TF as well as the alternatively spliced TF in endothelial and blood cells."

(The Dutch team specifically mentioned "elevated concentrations of tissue factor", without giving a cause.)

Cancer is a chronic inflammatory state - this is due to NF-kB (nuclear factor-kappaB) activation.

When we are under bacterial or viral attack, there is a danger that cell death (apoptosis) might outstrip cell division.  NF-kB is activated to get us through the crisis.  First there is a moratorium on cell death.  Next there is the production of COX/LOX enzymes that act on arachidonic acid to trigger the production of inflammatory metabolites.  A large number of other pro-survival proteins are also produced.

NF-kB isn't supposed to be chronically activated, but that's what happens in cancer.

The following paper [3] connects cancer, inflammation & coagulation from the perspective of thrombin.  "Pathologies at the nexus of blood coagulation and inflammation: thrombin in hemostasis, cancer, and beyond".  Of interest are the following sections:

a) "Thrombin in acute and chronic inflammatory processes"

b) "Thrombin in cancer and tumor biology"

c) "How does thrombin influence tumor biology?"

Rudolf Virchow (1821-1902), (who coined the terms thrombosis & embolism,) observed that certain cancers involved inflammation [4].

"It was only towards the end of the 20th century that Virchow's theory was taken seriously.[42] It was realised that specific cancers (including those of mesothelioma, lung, prostate, bladder, pancreatic, cervical, esophageal, melanoma, and head and neck) are indeed strongly associated with long-term inflammation.[43][44] In addition it became clear that long-term use of anti-inflammatory drugs, such as aspirin, reduced cancer risk.[45] Experiment also shows that drugs that block inflammation simultaneously inhibit tumour formation and development.[46]"

... continued in my aspirin post.

-Patrick

[1] ncbi.nlm.nih.gov/pubmed/106...

[2] ncbi.nlm.nih.gov/pubmed/268...

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

[4] en.wikipedia.org/wiki/Rudol...

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  • There was a news article online just a couple of days ago about the role a very low dosage of aspirin can play in both cancer prevention and reducing additional metastases in those who have advanced cancer.     And reduced mortality with advanced prostate cancer.

    And in my opinion, it may be a simpler explanation as to the mechanism---it makes the circulating tumor cells less "sticky," and less likely to take root, like weeds in a lawn.

    And the effective dosage was very low---being 1/5 the normal dose of aspirin.     It's amazing how this wonder drug, which was discovered so long ago, has so many uses.

    I never liked the other NSAIDS, with their possible liver damage.     And yet ask for an aspirin when hospitalized, and it's as if you're asking for heroin, or some other illicit drug.      I've always preferred aspirin over Tylenol or other OTC painkillers.

    CERICWIN

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