As one of the 12 factors responsible for blood clotting, fibrinogen is essential for the body’s healing processes that we often take for granted. However, high levels of fibrinogen can be harmful to your health. Keep reading to learn about how fibrinogen can help or hurt the body, and how you can increase or decrease your fibrinogen levels naturally.
- What Is Fibrinogen?
- Roles of Fibrinogen
- Normal Fibrinogen Levels
- Fibrinogen Blood Tests
- Low Fibrinogen Levels
- Causes of Low Fibrinogen
- Conditions Associated with Low Fibrinogen
- Ways to Increase Fibrinogen
- High Fibrinogen Levels
- Causes of Elevated Fibrinogen
- Consequences of Elevated Fibrinogen
- Ways to Decrease Fibrinogen
- Dysfunctional Fibrinogen
- Limitations and Caveats
- Drug Interactions
- Fibrinogen Genes
What Is Fibrinogen?
It circulates throughout the bloodstream in concentrations of 2 g/L to 4 g/L, by far the highest concentration of any blood clotting factor. Each protein breaks down after about 6 days in the bloodstream [R].
Roles of Fibrinogen
1) Fibrinogen Creates Blood Clots
Blood clots are extremely important to our health because they stop excessive blood loss and initiate the wound healing process [R].
In the process of coagulation (clotting), protein strands and cell fragments (platelets) combine together to form a hardened clot. This newly formed clot plugs the site of the wound, preventing further bleeding while the blood vessel continues to bend and stretch around the site [R].
Blood clot formation occurs through a series of steps:
- During injury, fibrinogen is cut by the enzyme thrombin into fibrin strands [R].
- Next, enzyme factor XIII (activated by thrombin) cross-links the fibrin strands to create a net that, along with platelets, forms a blood clot [R].
- The fibrin strands also bind to thrombin to prevent it from cutting up more fibrinogen, thereby inhibiting continuous clot formation [R].
- Fibrinogen further contributes to clot formation by binding to receptors on the surface of platelets and bridging them together [R, R].
2) Fibrinogen Regulates the Breakdown of Blood Clots
Fibrinogen and its successor fibrin both affect the breakdown of clots (fibrinolysis) [R].
3) Fibrinogen Is Involved in Immune Defense and Healing
Similarly, a study in mice with acetaminophen-induced liver damage found that fibrinogen enhanced liver repair by activating white blood cells [R].
Normal Fibrinogen Levels
Fibrinogen blood levels vary in the general population and range from 1.5 to 3.5 g/L, with average levels varying by geographical region [R].
Fibrinogen Blood Tests
Common Clotting Tests
These popular tests measure how long it takes blood to clot. Abnormally long times indicate a problem in clot formation, such as low levels of functional fibrinogen [R].
However, these tests measure a number of different protein interactions, so their results do not necessarily correlate with fibrinogen levels, nor are they sensitive to mild fibrinogen deficiency or dysfunction [R].
- Prothrombin Time (PT) measures the time it takes blood to clot after stimulating it with proteins that are released by damaged cells [R].
- A normal range for the PT is 10 to 14 seconds [R].
- Partial Thromboplastin Time (PTT) measures the time it takes blood to clot after adding a protein called factor XII, which stimulates the internal clotting pathway [R].
- A normal range for the PTT is 25 to 35 seconds [R].
Fibrinogen-Specific Clotting Tests
- Thrombin Time (TT) measures the time it takes fibrinogen to be converted into fibrin by adding thrombin. It is sensitive to mild fibrinogen deficiency and dysfunction but is affected by other factors that inhibit thrombin, such as medication [R].
- A normal range for the TT is 12 to 14 seconds, with longer times indicating a deficiency in properly functioning fibrinogen [R].
- Reptilase Time (RT) also measures the conversion of fibrinogen to fibrin but using snake venom instead of thrombin. It is therefore as sensitive as the Thrombin Time test and not affected by medication [R].
- A normal range for the RT is 18 to 22 seconds with longer times indicating functional fibrinogen deficiency [R].
Fibrinogen Level Tests
The amount of fibrinogen circulating in the blood is measured indirectly by the two methods described below. Doctors often use these tests together to determine if extended TT or RT times are due to deficiency or dysfunctional fibrinogen [R].
Equal levels of functional and immunological fibrinogen indicate low fibrinogen [R].
More immunological fibrinogen indicates dysfunctional fibrinogen [R].
- The Clauss Assay (or Functional Fibrinogen Assay) determines the amount of fibrinogen in a sample by comparing the TT of that sample to the TTs of other blood samples with known fibrinogen levels [R].
- The Fibrinogen Antigen Test (or Immunological Fibrinogen Assay) measures how much fibrinogen is present in the blood by the presence of fibrinogen antibodies [R].
Low Fibrinogen Levels
According to the World Federation of Hemophilia, low fibrinogen blood levels account for about 7% of bleeding disorders worldwide and this is more common in women than men [R].
Causes of Low Fibrinogen
Acquired hypofibrinogenemia, defined as fibrinogen deficiency developed later in life, is most often caused by excessive blood loss. This is because most of the body’s fibrinogen has been used up to stop the bleeding [R].
Blunt trauma to the liver specifically impaired fibrinogen production in pigs, leading to a decline in fibrinogen levels [R].
Urokinase decreased blood fibrinogen levels by an average of 35% in a study of 204 patients with stroke after 24 hours [R].
The anti-seizure (epileptic) drugs valproic acid (meta-analysis of 11 studies, 967 participants) and phenobarbital reduced blood fibrinogen concentrations in humans and animals, but the mechanisms remain unclear [R, R].
A 2-week regime of anabolic steroids reduced blood fibrinogen levels by 22% in a clinical trial of 14 healthy adults [R].
Leukemia may reduce fibrinogen levels by promoting clot formation and fibrinogen degradation (surveys of 1,304 patients, 17 patients, and 379 patients). As a result, hypofibrinogenemia (fibrinogen deficiency) may serve as an early marker for leukemia diagnosis [R, R, R].
4) Genetic Disease
Congenital hypofibrinogenemia is characterized by low blood levels of fibrinogen (between 0.5 and 1.5 g/L) with prolonged clotting times [R].
Caused by either a dominant or recessive mutation, this condition is estimated to affect as many as 1 people per 100. Many of these people present no symptoms, maintaining enough fibrinogen to clot minor injuries (survey of 100 patients; genomic database analysis including approximately 140,000 people) [R, R, R, R].
5) Congenital Afibrinogenemia
Congenital afibrinogenemia is characterized by extremely low blood levels of fibrinogen, (less than 0.1 g/L). Clotting time is unable to be determined because the blood never clots [R].
It is a recessive disease, meaning that both parents must have the genetic mutation for their child to acquire the disorder, which affects approximately 10 people per million in the general population. Afflicted individuals are typically diagnosed as infants (survey of 155 participants; genomic database analysis including approximately 140,000 people) [R, R, R].
6) Fibrinogen Storage Disease
Conditions Associated with Low Fibrinogen
Low Fibrinogen Causes Excessive Bleeding and Slow Healing
The most common symptoms of low blood fibrinogen levels are prolonged bleeding and easy bruising, especially after traumatic injury or surgery [R].
People with very low blood levels of fibrinogen also likely to have spontaneous bleeding, especially around the gums and joints [R].
Low Fibrinogen Causes Pregnancy Complications
Low Fibrinogen Causes Harmful Blood Clots
Paradoxically, people with extremely low fibrinogen levels may actually be more susceptible to free-floating clots that block blood vessels. This may be because fibrinogen is not present to inhibit the formation of these internal clots [R, R, R, R].
Ways to Increase Fibrinogen
1) Fibrinogen Replacement Therapy
Depending on the region, replacement therapy may come in the form of plasma (blood)-derived fibrinogen concentrate of cryoprecipitate (frozen plasma containing high concentrations of fibrinogen) [R, R].
A survey of 1,854 people found that people with elevated blood levels of cholesterol and fatty acids also had high fibrinogen levels, indicating a diet that raises cholesterol may also increase fibrinogen [R].
Protein, in particular, may be necessary for healthy levels of fibrinogen. Protein-deficient animals have low fibrinogen compared to their properly-nourished counterparts [R].
A study of 16 individuals also found that fibrinogen increased by 20 to 40% directly after the participants drank a protein shake or balanced-meal shake, but not after drinking water [R].
High Fibrinogen Levels
Causes of Elevated Fibrinogen
Multiple studies (9,127 participants; 200 participants; 11,059 participants) have found that smokers and ex-smokers have significantly higher fibrinogen levels than non-smokers (up to 53% more fibrinogen, and up to 11% more, respectively) [R, R, R].
The more a person smokes seems to further increase fibrinogen, and fibrinogen levels do not return to normal until a person has refrained from smoking for 15 years (11,059 participants; 118 participants) [R, R].
4) Birth Control
Estrogen may elevate fibrinogen by increasing the expression of the FGG gene and production of the protein, as seen in rats [R].
As shown in a study with 194 participants, this effect was compounded in women who smoked while on birth control [R].
5) Genetic Mutations
Multiple studies (895 participants; 1,002 participants; 7,329 participants) estimated that genes account for 34 to 46% of the variation in fibrinogen levels. A number of mutations associated with high fibrinogen levels are discussed below [R, R, R].
The inherited disorder homocystinuria increased blood levels of the amino acid homocysteine (3,216 participants), which lab experiments suggest may inhibit the breakdown of fibrinogen, leading to elevated levels [R, R, R].
Multiple studies (9,127 participants; 72 participants; 12 participants; 3,967 participants) have found that older people tend to have higher levels of blood fibrinogen, with concentrations increasing around 0.1-0.2 g/L each decade [R, R, R, R].
7) Cold Temperatures
Cold temperatures increase fibrinogen levels, resulting in chronic elevation during the winter months (2-hour study with 12 participants; yearlong study of 1,002 participants; yearlong study of 24 participants) [R, R, R, R].
Elevated fibrinogen of 206 Japanese emigrants in Hawaii was associated with more iron and sugar consumption. This could implicate the prevalence of meat and high glycemic foods in the Western diet, which is also associated with cardiovascular disease [R].
A survey of 1,854 people found that high fibrinogen was associated with low blood concentrations of minerals and vitamins, such as iron and vitamin B6, as well as high levels cholesterol and fatty acids. This suggests that both under- and overnutrition can increase fibrinogen [R].
A study of 16 individuals also found that fibrinogen increased by 20 to 40% directly after the participants drank a protein shake or balanced-meal shake, but not after drinking water [R].
Consequences of Elevated Fibrinogen
Fibrinogen Promotes Inflammation
Certain types of bacteria (Streptococcus) bind to fibrinogen in order to promote inflammation during infection [R].
Therefore, therapies to decrease fibrinogen/white blood cell binding may improve symptoms of common inflammatory diseases like rheumatoid arthritis, multiple sclerosis, and bacterial infection [R, R, R, R].
High Fibrinogen Increases the Risk of Harmful Blood Clots
High fibrinogen is associated with higher rates of heart disease, blood vessel dysfunction, and stroke. By some estimates, high fibrinogen predicts these diseases as well as high blood pressure and smoking [R, R, R, R].
In a study of 1,363 patients, high fibrinogen levels were also associated with a greater risk of developing heart disease within 18 months [R].
Furthermore, a longitudinal study of 158 participants concluded that people with larger fibrinogen spikes due to stress had poor blood vessel health, and therefore a greater risk of heart disease 3 years down the road [R].
Fibrinogen and its degradation by-products were also found in the plaque and cholesterol that builds up on the walls of blood vessels and can cause blockage [R].
High Fibrinogen May Harm the Brain
Fibrinogen may increase brain deterioration in Alzheimer’s disease. Lab and rat experiments found that by binding to the abnormal brain plaque, fibrinogen increased damage to brain cells and blood vessels, while also promoting inflammation [R, R, R, R].
Fibrinogen also suppressed the brain’s ability to heal itself in lab experiments. It did this by inhibiting the regeneration of brain cells and the protective myelin sheaths that normally cover them [R, R].
High Fibrinogen Is Associated with Diabetes and Its Complications
In a case-control study, 6 diabetic patients had high levels of both fibrinogen and glucagon, the hormone responsible for increasing blood sugar, but normal levels of albumin, a marker of insulin resistance. In other words, elevated fibrinogen may precede and possibly contribute to the development of diabetes [R, R].
High Fibrinogen May Promote Cancerous Tumors
High Fibrinogen Is Associated with High Blood Pressure
A longitudinal study of 143 subjects over 3 years found that increased fibrinogen after a stressful task predicted the later development of high blood pressure, while those whose fibrinogen levels remained stable did not develop high blood pressure. For unknown reasons, this effect was found exclusively in women [R].
Ways to Decrease Fibrinogen
1) Cholesterol Medication and Diet
A meta-analysis of 22 trials and 2,762 participants found that fibrate cholesterol medication most effectively reduces fibrinogen compared to statins [R].
Foods that improve bad (LDL) cholesterol may also decrease fibrinogen levels, such as healthy fats and dietary fiber [R].
2) Drugs That Slow Blood Clotting
3) Fish Oil
A double-blind cross-over study of 20 participants found that 6 grams per day of fish oil reduced fibrinogen by 20% after 6 weeks [R].
Another study of 25 participants found that three grams per day of fish oil for 4 weeks reduced fibrinogen blood levels by 3% on average [R].
It seems that strenuous exercise, in particular, reduces fibrinogen: 2 studies of 156 (ten weeks) and 8 participants (one week) showed that fibrinogen decreased by 10 to 20% after intense workouts [R, R].
Turmeric, a known remedy for inflammation and heart disease, decreased blood fibrinogen levels in a study of 30 subjects. Fibrinogen can also bind to curcumin (the active ingredient in turmeric) so that it does not degrade as quickly in the bloodstream [R, R].
6) Traditional Chinese Medicine
The traditional Chinese medicines Quyu Jiedu, Xuebijing treatment, and XueFu ZhuYu decoction, reduced blood fibrinogen levels in 2 meta-analysis studies (15 RCTs with 1,364 patients; 11 RCTs with 686 patients) evaluating the use of traditional Chinese medicine for high blood pressure and chest pain from heart disease [R, R].
7) Moderate Alcohol Consumption
Multiple studies (117 participants for 1 month; 20 participants for 6 weeks; 11 participants for 12 weeks) have shown that daily moderate alcohol consumption (wine or beer) reduced blood fibrinogen levels [R, R, R].
A glass of red wine a day for 40 days was seen to decrease blood fibrinogen levels by 8 to 15% in a clinical trial of 69 healthy adults [R].
8) Olive Oil
In a double-blind cross-over study, 6 grams of olive oil per day reduced blood fibrinogen levels by an average of 18% in 20 healthy volunteers after 6 weeks [R].
9) Nattokinase (Fermented Soybean)
A study of 12 healthy participants found that a single dose of 2000 nattokinase, an enzyme derived from fermented soybeans, significantly decreased blood fibrinogen levels after only 4 hours [R].
10) Anabolic Steroids
A 2-week regimen of anabolic steroids reduced blood fibrinogen levels by 22% in an experiment with 12 healthy adults [R].
11) Hormone Replacement Therapy
Multiple studies (DB-RCT of 152 women for 1 year; 29 women for 6 months; survey of 4,837 women; survey of 300 women) have found that hormone replacement therapy may help reduce fibrinogen levels in postmenopausal women, though the effect appears to be minimal [R, R, R, R].
12) B Vitamins
A study (RCT) of 24 adults found that 5 mg/day of vitamin B9 for 4 weeks reduced blood fibrinogen levels by an average of 9% [R].
A 4-week regime of vitamin B6, B9, and B12 also reduced blood fibrinogen levels in 21 patients with sepsis [R].
Dysfibrinogenemia comprises of cases in which individuals have normal levels of fibrinogen but structural abnormalities that do not allow the molecule to function properly [R].
Approximately 55% of individuals with this disorder are asymptomatic (present no symptoms), while 25% suffer from excessive bleeding, and the remaining 20% have excessive clotting [R].
Congenital dysfibrinogenemia is typically autosomally dominant, meaning that only one parent needs to have the gene for their child to inherit the disorder. Afflicted individuals are typically diagnosed as adults, possibly after they have passed it on to their children [R, R].
Because of this and the large percentage of asymptomatic carriers, it is hypothesized to affect 1 person per 100 in the general population [R].
It is autosomally dominant, and likely more common than afibrinogenemia (extremely low blood fibrinogen) and hypofibrinogenemia(low blood fibrinogen) in the general population [R].
This disorder sometimes coexists with plaque build-up in the kidneys that eventually leads to kidney failure [R].
Hereditary Renal Amyloidosis
Limitations and Caveats
Furthermore, most of the causal relationships between fibrinogen concentration and associated diseases remain unclear.
More research is needed to make concrete conclusions about the effects of and effects on fibrinogen.
On the other hand, an anticoagulant such as heparin, aspirin, or Lepirudin is recommended in conjunction with fibrinogen replacement therapy to help reduce the likelihood of an internal blood clot [R].
Three different genes than encoding fibrinogen (FGA, FGB, and FGG) are used to produce the three chains that compose fibrinogen, Aα, Bβ, and γ [R].
Common alternative expressions of the FGA and FGG genes result in the functional fibrinogen subtypes AαE and γ’, respectively [R].
rs146387238 (C>A / C>G) is associated with afibrinogenemia (very low blood fibrinogen levels) [R].
rs1800790 (G>A) (minor allele) is associated with high fibrinogen, as well as reduced inflammatory response and increased risk of heart disease, likely because this sequence affects the production of the entire FGB gene [R, R, R, R].
rs2227399 (G>T) is associated with high blood fibrinogen levels [R].
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