There are several biomarkers that are useful to follow during and after cancer treatment. The first one we’ll discuss today is coagulation, which relates to the clotting of blood. So what does coagulation have to do with cancer?

What are biomarkers?

Before we look at specific biomarkers, let’s begin with discussing what biomarkers are. A biomarker is something that is measurable inside of us that can be indicative of a physiological state or disease state. It can be used to see how well a body responds to treatment or monitored to see how a disease is progressing or regressing.

The simplest biomarkers are things like our weight, height, body measurements, hair graying, etc. Other biomarkers may be derived from our blood, urine, or saliva. Examples include blood glucose levels, or C-reactive protein (CRP) level as a measure of inflammation, or CA-125, which is a biomarker for ovarian cancer and other cancers.   Scans, such as mammograms or MRIs, are also considered biomarkers.  

Biomarkers are typically easy to measure and can be very useful indicators. But most biomarkers are general, and thus can create a picture of what might be happening, but they don’t diagnose something specific. If biomarker levels change or fall out of normal limits, this indicates that we should do further specific investigations, especially if these changes are associated with symptoms. 

Now lets look in more detail at coagulation as a biomarker and its usefulness.

What is coagulation?

Coagulation is important for our health. It is the process by which blood changes from a liquid into a gel, forming a clot. Coagulation factors, fibrin, and platelets (a type of white blood cell) are all involved in forming a clot. Blood clots help us handle injuries by stopping or preventing bleeding. Coagulation is also involved in the immune system as the clots can trap microbes in the blood.

However, blood clots can also cause problems when they occur in blood vessels or the heart. Such clots cause a blockage known as thrombosis. (The medical term for a blood clot is a thrombus.) Examples of diseases associated with thrombus formation include deep vein thrombosis,  stroke, and heart attacks.

Thrombosis is the result of too much coagulation; there are also situations where we can have too little coagulation, such as in hemorrhages or hemophilia, where blood does not clot properly and can lead to excessive bleeding. 

Why is it important to look at coagulation?

Coagulation disorders are common in cancer patients and, unknown to many, thrombosis (a blood clot and type of coagulation disorder) is the second most frequent cause of death in cancer patients [1]. Additionally, more than 40% of patients who receive chemotherapy have coagulation disorders.

We can therefore see that this over-coagulation, known as hypercoagulation, accounts for a significant percentage of mortality and morbidity in cancer patients. Yet coagulation is not a standard parameter that oncologists routinely monitor. Given the risks involved with hypercoagulation, it would seem prudent not to wait until a serious coagulation event occurs (such as stroke or heart attack) but rather monitor the situation beforehand, taking action where needed to prevent an event. 

How does cancer relate to coagulation?

Tumor cells produce factors that promote coagulation. They like to surround themselves with these factors – such as fibrin – which acts as a sort of net around the tumor, blocking access to the tumor by immune cells (see the illustration above with the string-like fibrin around the red blood cells and platelets).

If this occurs, anti-coagulant therapies can help break down that fibrin and expose the tumor to the immune system, and thus make the tumor more susceptible to immune attack.
 
High levels of coagulation biomarkers correlate with worse prognosis in many cancers, including colorectal, prostate, breast, endometrial, ovarian, gall bladder, pancreatic, and renal cell carcinomas. Increased coagulation also consistently correlates with tumor progression, metastases, and worse clinical outcomes. Coagulation is, therefore, an important factor in people diagnosed with cancer.

Do cancer treatments affect coagulation?

Coagulation might also be increased as a result of some cancer treatments such as diagnostic procedures, surgery, chemotherapy, radiotherapy, hormonal treatments and biological therapies. 

Additionally, coagulation can affect the effectiveness of cancer treatments. If hypercoagulation exists, with a fibrin “net” around the tumor, not only can that block the immune cells from attacking the tumor, but it can also block accessibility of the tumor by chemotherapies and other therapies. This blockage means that the benefit of these therapies might be lost or reduced. 

How do you monitor coagulation?

Now we see the value in monitoring coagulation to reduce risk of thrombosis, so how do we measure it?   There are a few different measurements of coagulation. 

General:

  • If the results of a complete blood count (CBC) show that there are elevated platelet counts (a type of white blood cell), this could indicate a pro-coagulation state. Platelet cells are the ones that clump together to form the sticky mass that helps the blood to clot. In addition to cancer, high platelet counts may also be seen with many other conditions including anemia, rheumatoid arthritis, inflammatory bowel disease, tuberculosis, use of oral contraceptives. Temporary high levels are seen after surgery, physical activity, and excessive alcohol consumption. 
  • C-reactive protein (CRP) is a general measure of inflammation in the body. We want levels to be less than 1.0mg/l, so if levels are higher, again, ask your doctor to do some additional tests. Elevations in CRP are involved in many different situations, as inflammation is key in many chronic illnesses. This is a non-specific test – but is useful along with other tests to fill out the picture of what is going on in the body.

More specific coagulation markers

  • Fibrinogen – this becomes broken down into fibrin by the enzyme thrombin to form clots. Levels should be less than 375 ng/ml, with an ideal value of 275-300 ng/ml.
  • D-dimer – this is a substance that is released when a blood clot breaks up.  Normal levels are < 250ng/ml D-dimer units. Higher levels might suggest hypercoagulation. 

Again, it is important to remember that elevated levels of any these markers are NOT diagnostic of cancer or cancer progression. Rather they should be used as an indicator that further examination/testing is necessary to figure out why the levels are raised, which could be for many reasons.

How often should you measure coagulation? 

It is useful to measure the above parameters at the time of cancer diagnosis to get baseline measurements. They should then be followed in all cancer patients. An idea of testing frequency is:

  • If in active treatment, monitor D-dimer and fibrinogen monthly.
  • After treatment has finished, monitor D-dimer and fibrinogen every three months for two years.
  • After two years post treatment, monitor levels every six months. 
  • For prevention, it might be useful to monitor D-dimer and fibrinogen levels annually in those with a higher risk of cancer (see below) and with previous history of coagulation issues, and from age 45 onwards, particularly as coagulation factors increase with age.  
  • For non-high risk, annual CBC and CRP should be part of your general annual health screen.  

By following this testing schedule, early intervention can take place if changes are seen, which can prevent coagulation getting worse. 

While you can order some of these tests independently, it is recommended that you work with your oncologist, doctor, health care provider, naturopath, cancer coach, or nutritionist to help with the interpretation of results. If testing indicates increasing coagulation, and you have a diagnosis of cancer, make sure to tell your oncologist.

Who is at higher risk for coagulation issues? 

Increased risk of coagulation issues is seen in anyone with:

  • cancer
  • cardiovascular disease
  • hypertension
  • clotting disorders 
  • in-dwelling catheter/port
  • a history of venous thromboembolism or pulmonary embolism
  • genetic polymorphisms or known hematologic risk factors for hypercoagulation
  • long-term use of certain medications such as tamoxifen
  • limited mobility or sedentary
  • obese
  • diabetic

What medications can help with hypercoagulation?

Medically, hypercoagulation can be managed with the use of low-molecular-weight heparin (LMWH). This is a prescription medication that your oncologist or physician can prescribe. Some studies suggest that LMWH has anti-tumor effects and improves overall survival in cancer patients. However, LMWH increases the risk for bleeding and has other adverse effects. Therefore, patients should be monitored closely.

Are there any natural products that can help?

A variety of natural interventions can offer the benefits of anticoagulation with fewer risks than LMWH. However, it should be noted that natural interventions have not been directly compared in studies against LMWH. These natural approaches may be more suitable for those just beginning to show changes in biomarkers. The biomarkers levels should be monitored as the intervention continues to see if it is helping. It is advised that you work with a physician, nutritionist, naturopath, or cancer coach rather than try and figure all this out alone.

Patients with a history of a blood clot should consider natural anticoagulation therapies only in collaboration with their oncologist/physician.  

The first strategies to try if you find that you are moving to a hypercoagulation state are: make sure you are well hydrated;  avoid being sedentary; begin an anti-inflammatory diet; and limit your alcohol intake.

The following natural interventions might help to decrease coagulation further (refer to a health practitioner for appropriate dose levels):

  • Proteolytic enzymes – for example, bromelain
  • Omega 3 fatty acids
  • Niacin
  • Vitamin C
  • Curcumin
  • Berberine
  • Resveratrol
  • Quercitin

Take home points

Thrombosis – an over coagulation issue, is the second leading cause of death in cancer patients.

Simple blood tests can monitor levels of coagulation biomarkers to see if you are over-coagulating and thus at increased risk of thrombosis.

Early detection of coagulation issues enables early treatment and thus reduces risk of a hypercoagulation disorder. 

If your oncologist doesn’t monitor coagulation, work with another health provider to keep track of it. 

[1].  Caine, G. J., Stonelake, P. S., Lip, G. Y., & Kehoe, S. T. (2002). The Hypercoagulable State of Malignancy: Pathogenesis and Current Debate.Neoplasia (New York, N.Y.), 4(6), 465–473. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1550339/

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