Elevated Fibrinogen: Risk factor for blood clots

Fibrinogen is essential for making blood clots, but high levels of fibrinogen are linked to several health conditions.

This article explains why fibrinogen levels are important and then shows you how to check your genetic data to see if you are likely to have genetically higher fibrinogen.

Fibrinogen, Heart Health, and Genetics:

  • Fibrinogen is a glycoprotein that helps platelets come together and form blood clots. Genetics accounts for about 50% of the variability in fibrinogen levels (the rest is diet, lifestyle, overall health).[ref]
  • Fibrinogen is mainly produced by the liver, but the epithelial cells lining the lungs and intestines can also produce fibrinogen. Tumor cells also have been shown to produce fibrinogen.[ref]
  • Levels of fibrinogen rise during systemic inflammation.

Making a clot from fibrinogen:

For a clot to form, an enzyme called thrombin is needed to convert fibrinogen into fibrin, forming the fibrous part of a blood clot.

The fibrin strand crosslinks with each other using factor XIIIa to form a clumped network of fibrin.

A blood clot doesn’t just form and sit there forever (obviously). Instead, it is a dynamic event with the clot-forming and breaking down all the time.  Plasmin, an enzyme that breaks down clots, and fibrin activate the formation of plasmin. When plasmin breaks down some of the fibrin, the d-dimer is released. (D-dimer levels are often tested in hospitals to see if there has been a clot.)

Inflammation and Fibrinogen

  • In addition to its role in clotting, fibrinogen is activated by acute inflammation (whether from a wound or from other sources).[ref]
  • Fibrinogen production in the liver immediately increases in acute inflammatory situations.
  • Additionally, fibrinogen causes macrophages to produce inflammatory cytokines.[ref]

Thus, fibrinogen is created in response to inflammation and can also cause an increase in inflammation under certain conditions.

Fibrinogen in Heart Disease

One of the key players in cardiovascular disease (CVD) is plasma fibrinogen. It is a main component of clots in the arteries. In general, fibrinogen levels are higher in people who have cardiovascular disease, and the higher the fibrinogen level, the greater the mortality risk.[ref]

Cardiovascular disease ‘endpoints’ in research are defined as things like stroke, heart failure, coronary heart disease, and peripheral artery disease. Some researchers believe that fibrinogen levels in CVD reflect the increased inflammation that accompanies heart disease. Thus, the increased inflammation causes high fibrinogen, which then adds to atherosclerosis (plaque in the arteries).[ref]

Genetic variants that increase fibrinogen increase the risk of heart disease. But lifestyle factors play a big role here — smoking, diet, lack of exercise all increase inflammation and thus raise fibrinogen levels. For example, cigarette smoking increases fibrinogen by over 10%.[ref]

The use of Mendelian randomization studies try to determine whether something causes a disease (e.g. does higher fibrinogen cause cardiovascular disease vs. does CVD cause higher fibrinogen).  A Mendelian randomization study on fibrinogen-related genes found that fibrinogen does have a small causal role in CVD.[ref]  Again – this points to genetics + lifestyle factors.

Coagulation in COVID-19

Doctors and researchers have found that people who have severe COVID-19 are likely to have hypercoagulation – too much clotting going on relative to the breaking down of clots.[ref]

  • Patients with prothrombin time >3s were at a 4-fold risk of having a ‘thrombotic event’, which included stroke, heart attack, deep vein thrombosis, or pulmonary embolism.[ref]
  • Another study found elevated D-dimer levels and increased prothrombin time were predictive of mortality in COVID-19 patients in the hospital.[ref]
  • A July 2020 study showed increased fibrinogen levels and ‘dramatically increased’ D-dimer levels in COVID-19 patients. CRP, Factor VIII, and von Willebrand factor – all involved in clotting – were also increased.[ref]

There are several theories as to what is going on with abnormal coagulation in COVID-19:

  • First, plasmin (the enzyme that breaks down clots) activates whenever fibrinogen is activated to make a clot.  Plasmin can also enhance the pathogenicity of certain viruses – and researchers think that this is possible with the SARS-CoV-2 virus.[ref]
  • Second, severe COVID-19 patients have increased pro-inflammatory cytokine levels. These inflammatory cytokines then tip the balance towards too much coagulation and not enough anti-coagulation.[ref]

Most patients now are started on anti-coagulants when in the hospital for COVID-19.[ref]

Fibrinogen levels in cancer

Fibrinogen levels show an elevation in certain types of cancer. Higher fibrinogen levels in lung cancers, such as NSCLC and mesothelioma, are predictive of outcome.[ref][ref] A study of women with uterine leiomyosarcoma, a rare uterine cancer, showed that patients with higher fibrinogen levels had a much lower rate of survival.[ref]

Additionally, there may be a small causal role here. People with higher fibrinogen levels are also at a higher risk of lung cancer. Researchers think this is because increased coagulation could be a cause of lung cancer.[ref]

Stress and Fibrinogen:

Both mental stress and cellular stress can increase fibrinogen levels. Acute and chronic mental stress can increase inflammation levels throughout the body, and this results in higher fibrinogen levels.[ref]

Three proteins in Fibrinogen:

The fibrinogen molecule is composed of three different amino acid chains – α, β, and γ.[ref] These components come together to form the fibrinogen molecule circulating in the bloodstream, and when a coagulation event occurs, they break up to form the fibrin.

There are three genes that code for the three components of fibrinogen – FBA, FGB, and FGG. All three of these genes have genetic variants affecting fibrinogen levels in different ways.

 


Genetic variants in fibrinogen genes:

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Additive Risk:
Studies on thrombotic events, such as stroke and deep vein thrombosis (DVT), show that carrying a combination of variants that increase fibrinogen can add together to increase risk. Additionally, variants in the F5 (Factor V) gene and the F2 (prothrombin) gene add to the risk with the fibrinogen variants.[ref]

FGA gene:

Check your genetic data for rs6050 Thr312Ala (23andMe v4, v5):

  • C/C:  increased risk of chronic thromboembolic pulmonary hypertension, more resistant to anticoagulation therapy[ref]; increased risk of stroke (2-fold)[ref]; increased risk of DVT[ref]; higher D-dimer levels[ref]
  • C/T: typical risk of stroke; increased risk of DVT
  • T/T: typical

Members: Your genotype for rs6050 is .

Check your genetic data for rs2070022 (23andMe v4; AncestryDNA):

  • G/G: typical
  • A/G: decreased fibrinogen levels
  • A/A: decreased fibrinogen levels[ref]

Members: Your genotype for rs2070022 is .

FGB gene:

Check your genetic data for rs1800787 C148T(23andMe v4; AncestryDNA):

  • C/C: typical
  • C/T: increased risk of ischemic stroke, increased risk of cardiovascular disease, increased fibrinogen
  • T/T: increased risk of ischemic stroke[ref]; increased risk of cardiovascular disease[ref] increased fibrinogen levels, exacerbated by inflammation (IL-6) [ref]

Members: Your genotype for rs1800787 is .

Check your genetic data for rs1800789 (23andMe v4, v5; AncestryDNA):

  • A/A: increased fibrinogen levels[ref]; exacerbated by inflammation (IL-6) [ref]
  • A/G: increased fibrinogen levels, exacerbated by IL6
  • G/G: typical

Members: Your genotype for rs1800789 is .

FGG genes:

Check your genetic data for rs2066865 (23andMe v4, v5; AncestryDNA):

  • G/G: typical
  • A/G: typical risk for DVT; somewhat increased fibrinogen
  • A/A: increased fibrinogen; increased risk for DVT[ref][ref]

Members: Your genotype for rs2066865 is .

Check your genetic data for rs2066860 (23andMe v4, v5; AncestryDNA):

  • C/C: typical
  • C/T: increased triglycerides, part of a haplotype linked with DVT
  • T/T: increased triglycerides[ref], part of a haplotype linked with DVT[ref]

Members: Your genotype for rs2066860 is .

 


Lifehacks:

Fibrinogen is something that you need at the right levels in your body — too much can increase the risk of blood clots and too little could increase the risk of bleeding.

If you are on any medications, especially heart-related medications, talk with your doctor before adding in any supplements. 

Get active and stay active:
Mild to moderate exercise has shown to decrease fibrinogen levels.[ref]

Fish oil: 
Research has shown for decades that fish oil helps reduce clotting in some people — with an overall average decrease when you look at large groups. A study found that fish oil was really effective at reducing coagulation in people who had carried the rs6050 C- allele.[ref]

Olive oil:
One study showed that increasing olive oil consumption by 6 g per day was almost as effective as fish oil (also 6 g/d) at lowering plasma fibrinogen levels.[ref]

Lactobacillus plantarum:
A clinical trial showed that a probiotic, Lactobacillus plantarum 299v, lowered fibrinogen levels in healthy adults.[ref]

Nattokinase:
Supplemental nattokinase (or eating natto regularly) may help to lower fibrinogen levels. A study using 2000FU/capsule found that fibrinogen levels were lowered significantly after two months. [ref]

Decrease your stress:
Chronic mental stress increases fibrinogen levels (and cardiovascular disease risk). Adults with high morning cortisol levels also are very likely to have higher fibrinogen levels.[ref] Additionally, studies show that subjecting people to mental stress (job interview, mental math test in front of an audience) increases cortisol levels which correlated with an increase in fibrinogen.

A glass of red wine?
Moderate red wine consumption is linked to a small decrease in fibrinogen levels.[ref]


Related Genes and Articles:

Lipoprotein(a): A silent risk factor for heart attacks
High Lp(a) levels are a big risk factor for sudden heart attacks. Your Lp(a) levels are mainly controlled by your genetic variants. Check to see if you carry genetic variants that increase or decrease Lp(a).

Factor V Leiden and Blood Clots
The factor V Leiden genetic mutation significantly increases the lifetime risk of blood clots. Check your genetic data to see if you carry this mutation – and then learn to recognize the symptoms of blood clots.

7 genetic variants that increase your risk of blood clots
Blood clots are in the news these days due to increased numbers for people with COVID-19. Learn more about how genetic variants increase the risk of blood clots that can lead to DVT and pulmonary embolisms.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.