Human fibrinogen

Fibrinogen is a blood-clotting factor.  Most acute myocardial infarctions (heart attacks) are now known to be due to acute thrombosis, or the sudden formation of a blood clot at the site of an atherosclerotic plaque.  It makes sense, therefore, that elevated levels of fibrinogen, an acute phase protein that originates in the liver and is part of the coagulation cascade of proteins, would be associated with an increased risk of heart attack. It is converted to fibrin during the blood-clotting process (coagulation). The amount of fibrinogen in the plasma can be measured as a nonspecific indicator of whether or not an inflammatory process is present in the body. Elevated fibrinogen levels also contribute to an accelerated erythrocyte sedimentation rate (ESR), which can be used as another nonspecific indicator of inflammation. The ESR can be used, as the level of fibrinogen can be, to monitor the course of a chronic inflammatory process: decreases suggest improvement, while increases suggest worsening of the process. a sterile fraction of normal human plasma, dried from the frozen state, which in solution has the property of being converted into soluble fibrin when thrombin is added; administered by intravenous infusion to increase the coagulability of the blood.  This is a protein molecule that promotes clotting and also thickens the blood.  The more there is, the greater the likelihood that your heart is struggling to pump sludge.  High levels seem to correlate with cigarette smoking, obesity, inactivity, aging, and diabetes.  Levels above 350 double the risk of coronary disease.

The fibrinogen test aids in the diagnosis of suspected clotting or bleeding disorders caused by fibrinogen abnormalities.  This test is performed with a blood sample, which can be drawn at any time of day. The patient does not have to be fasting (nothing to eat or drink).  Because a fibrinogen test is often ordered when a bleeding disorder is suspected, the patient should apply pressure or a pressure dressing to the blood-drawn site site for a period of time after blood is drawn, and then reexamine the site for bleeding.  Risks for this test are minimal, but may include slight bleeding from the blood-drawing site, fainting or feeling lightheaded after procedure, or the seeing the accumulation of blood under the puncture site (hematoma). This test is not recommended for patients with active bleeding, acute infection or illness, or in those patients who have received blood transfusions within four weeks.

Fibrinogen, unlike CRP (which is thought to be merely a marker for inflammation,) is thought to play a direct role in coronary artery
thrombosis.  Ideally, therefore, when fibrinogen levels are high, reducing those levels should be the goal of therapy. Unfortunately, at the present time, there are no known therapies that reduce fibrinogen levels.  So what good is it?  What should doctors and patients do when fibrinogen levels are elevated?

Drugs that may increase fibrinogen levels include estrogens and oral contraceptives. Drugs that may cause decreased levels include anabolic steroids, androgens, phenobarbital, urokinase, streptokinase, and valproic acid.

Fibrinogen plays two essential roles in the body: it is a protein called an acute-phase reactant that becomes elevated with tissue inflammation or tissue destruction, and it is also a vital part of the "common pathway" of the coagulation process.  In order for blood to clot, fibrinogen must be converted to fibrin by the action of an enzyme called thrombin. Fibrin molecules clump together to form long filaments, which trap blood cells to form a solid clot.

The conversion of fibrinogen to fibrin is the last step of the "coagulation cascade," a series of reactions in the blood triggered by tissue injury and platelet activation.  With each step in the cascade, a coagulation factor in the blood is converted from
an inactive to an active form. The active form of the factor then activates several molecules of the next factor in the series, and so on, until the final step, when fibrinogen is converted into fibrin.

The factors involved in the coagulation cascade are numbered I, II, and V through XIII. Factor I is fibrinogen, while factor II (fibrinogen's immediate precursor) is called prothrombin. Most of the coagulation factors are made in the liver, which needs an adequate supply of vitamin K to manufacture the different clotting factors.

When fibrinogen acts as an "acute-phase reactant," it rises sharply during tissue inflammation or injury. When this occurs, high fibrinogen levels may be a predictor for an increased risk of heart or circulatory disease. Other conditions in which fibrinogen is elevated are cancers of the stomach, breast, or kidney, and inflammatory disorders like rheumatoid arthritis.
 
 

Reduced fibrinogen levels can be found in liver disease, prostate cancer, lung disease, bone marrow lesions, malnourishment, and certain bleeding disorders. The low levels can be used to evaluate disseminated intravascular coagulation (DIS), a serious medical condition that develops when there is a disturbed balance between bleeding and clotting. Other conditions related to decreased fibrinogen levels are those in which fibrinogen is completely absent (congenital afibrinogenemia), conditions in which levels are low pofibrinogenemia), and conditions of abnormal fibrinogen (dysfibrinogenemia). Obstetric complications or trauma may also cause low levels. Large-volume blood transfusions cause low levels because banked blood does not contain fibrinogen.
 

RELATED STUDIES

Fibrinogen depleting agents for acute ischaemic stroke 9 (Cochrane Review)
From The Cochrane Libary, Issue 4, 2001.
Prepared and published by Update Software Ltd. All rights reserved.

A substantive amendment to this systematic review was last made on 01 November 1996. Cochrane reviews are
regularly checked and updated if necessary.

Background: Fibrinogen depleting agents reduce fibrinogen in blood plasma, reduce blood viscosity and hence increase blood flow. This may help remove the blood clot blocking the artery and re-establish blood flow to the affected area of the brain after an ischaemic stroke . The risk of haemorrhage may be less than with thrombolytic agents.

Objectives: The objective of this review was to assess the effect of fibrinogen depleting agents in people with acute ischaemic stroke.

Search strategy: We searched the Cochrane Stroke Group trials register, Embase (to January 1996) and the Index of scientific and technical proceedings (1982 to 1996). We handsearched 10 Chinese journals and the proceedings of the 4th Chinese Stroke Conference (1995). We contacted Chinese and Japanese researchers, and drug companies.

Selection criteria: Randomised and quasi-randomised trials of fibrinogen depleting agents started within 14 days of stroke onset, compared with control in patients with definite or possible ischaemic stroke.     Data collection and analysis: Two reviewers independently applied the inclusion criteria, assessed trial quality and extracted the data.

Main results: Three trials involving 182 patients were included. All trials tested ancrod. Allocation concealment was adequate in two trials. Fibrinolytic therapy appeared to reduce the number of deaths during the scheduled treatment period (odds ratio 0.33, 95% confidence interval 0.13 to 0.85). There was no difference in death from all causes at the end of follow-up (odds ratio 0.57, 95% confidence interval 0.27 to 1.23). The risk of haemorrhage appeared to be small, but there were too few data to be conclusive. One trial in 132 people showed a statistically non-significant decrease in the odds of being dead or disabled at the end of follow-up (odds ratio 0.52, 95% confidence interval 0.26 to 1.03).

Reviewers' conclusions: Although ancrod appears to be promising, it is not possible to draw reliable conclusions from the available data.

Citation: Liu M, Counsell C, Wardlaw J. Fibrinogen depleting agents for acute ischaemic stroke (Cochrane Review). In: The Cochrane Library, 4, 2001. Oxford: Update Software.

This is an abstract of a regularly updated, systematic review prepared and maintained by the Cochrane Collaboration. The full
text of the review is available in The Cochrane Library (ISSN 1464-780X).

High Fibrinogen Bad for the Heart

Elevated levels of fibrinogen, a protein synthesized by the liver which is necessary for normal blood clotting, increases the risk for cardiovascular disease (CVD) and may be the mechanism by which many recognized cardiac risk factors cause disease.

Researchers evaluated fibrinogen levels in participants of the Framingham Offspring Study, a long-term, ongoing study that has been investigating CVD risk factors since 1948.  Of 2,632 study subjects with available fibrinogen measurements, 267 had known cardiovascular disease.

Investigators evaluated the association between fibrinogen and traditional risk factors of CVD, including total and HDL cholesterol, diabetes, age, and cigarette smoking. They also compared two different methods of measuring fibrinogen levels.

One test was the newly developed "functional intact fibrinogen" (FiF) test and the other was the older Clauss assay, in which fibrinogen is converted to fibrin, then timed to determine how long it takes a clot to form. Patients with the highest levels of fibrinogen had a threefold greater risk of CVD than those with the lowest levels.  However, after adjusting for various risk factors, such as age,
body mass index, smoking, diabetes, total cholesterol, and triglycerides, only elevated fibrinogen levels measured with the FiF test was found to be significantly associated with established CVD. Fibrinogen is a good variable that is independently related to other CVD risk factors, lead author Ralph B. D'Agostino told WebMD. Dr. D'Agostino also emphasized that although there are limited method that can be used to try to lower fibrinogen levels, behavioral and lifestyle changes, such as quitting smoking, losing weight and becoming more physically active may help. The study was supported by grants from the National Institutes of Health and American Biogenetic Sciences, developer of the functional intact fibrinogen test. (Circulation: Journal of the American Heart Association October 3, 2000; 102: 1634)

DR. MERCOLA'S COMMENT: This information is not new as I posted a study on this two and a half years ago. However, many physicians, including cardiologists, rarely look at other blood risk factors than total cholesterol. The HDL/Cholesterol ratio and the Triglyceride/HDL ratio are two very powerful predictors of heart disease. One of the major ways one can improve these ratios, and also the fibrinogen level, is to normalize one's insulin levels with an optimized diet.  One interesting finding here is the apparent superiority of this new type of diagnostic test for fibrinogen levels, called the "functional intact fibrinogen" test. Maybe this new test
will convince more doctors to check this important blood parameter.
http://www.mercola.com/1997/nov/7/
cholesterol_drug_impairs_brain_function.htm
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C-reactive protein and fibrinogen - Newer risk factors for coronary artery disease (by Dr.Rich - dateline: 11/14/2000)

Recently, two new blood tests have been promoted as predictors of heart disease.  Both of these blood tests – C-reactive protein (CRP) and fibrinogen – have now been correlated with a significantly increased risk of future heart attacks.  The problem is, unlike other risk factors (such as obesity, smoking and cholesterol) it is not at all clear what should be done about high CRP and fibrinogen levels.

What are CRP and fibrinogen?

CRP is a protein released into the bloodstream any time there is active inflammation in the body. (Inflammation occurs in response to infection, injury, or various conditions such as arthritis.)  Evidence is accumulating that atherosclerosis (coronary artery disease) is an inflammatory process.  Some even think that coronary artery disease may be promoted by infection.  The fact that elevated CRP levels are associated with an increased risk of heart attack tends to support the proposed relationship between inflammation and atherosclerosis.

Fibrinogen is a blood-clotting factor.  Most acute myocardial infarctions (heart attacks) are now known to be due to acute thrombosis, or the sudden formation of a blood clot at the site of an atherosclerotic plaque.  It makes sense, therefore, that elevated fibrinogen levels (that is, a protein that promotes blood clotting) would be associated with an increased risk of heart attack.

Why all the interest in CRP and fibrinogen now?

Two reasons.  First, large studies were published this year that, essentially, “clinched” the relationship between these two blood proteins and the risk of heart attack.  And second, new commercial tests for measuring these proteins were developed.  (Aside to conspiracy theorists: this means there is money to be made by measuring them.) Thus, physicians now have a clinically relevant reason to do the tests, and a means for doing so.

Can high CRP and fibrinogen levels be treated?  The short answer is, no.

Regarding CRP levels, it is not the CRP level itself that is thought to be the problem, but the presumed inflammation in the coronary arteries that is reflected by the high CRP level.  So the real question is whether the inflammation (and not the CRP) can be treated.
There is some evidence that infection with an organism called Chlamydia pneumoniae may be a factor in the development of coronary artery disease.  If so, then antibiotics might be effective in eliminating the infection and reducing the risk of heart attacks (and, dentally, in reducing CRP levels).  But the only published trial testing whether antibiotics help to prevent heart attacks (in patients with serum markers for Chlamydia) showed no benefit. Two larger trials are underway, however.  If antibiotics should prove effective in the future, measuring CRP levels may turn out to be a useful screening tool to select patients who might benefit from antibiotic therapy.  Further, there is accumulating evidence that the statin drugs – drugs used to treat high cholesterol – may also have the effect of reducing inflammation in the coronary arteries.  Trials are underway to assess this possible beneficial effect of the statin drugs.  CRP levels may turn out to be a useful screening tool here, also.

Fibrinogen, unlike CRP (which is thought to be merely a marker for inflammation,) is thought to play a direct role in coronary artery
thrombosis.  Ideally, therefore, when fibrinogen levels are high, reducing those levels should be the goal of therapy. Unfortunately, there are no known therapies that reduce fibrinogen levels.

So what good are they?  What should doctors and patients do when CRP or fibrinogen levels are elevated?

Asked in another way, if there aren’t any specific treatments that can be used in response to elevated CRP or fibrinogen levels, why should they ever be measured?  (As Dr. Rich always tells his medical students: Never order a test when you know ahead of time you’re not going to know what to do with the results.)

At the moment, the only good answer to this question is: knowing the CRP and/or fibrinogen levels may help to more accurately characterize the risk of coronary artery disease, so the doctor and patient can decide how aggressive to be in attacking risk factors that can be changed.  For instance, both the patient and the doctor may be reluctant to begin statin drugs when cholesterol levels are only borderline elevated.  In this case, elevated CRP or fibrinogen levels may tip the scales in favor of beginning therapy, whereas normal CRP or fibrinogen levels may be tip the scales in favor of withholding therapy.  Measuring one or both of these new risk factors may therefore play directly into therapeutic decisions.

Conceivably, knowing that the CRP or fibrinogen level is elevated might be the straw that finally breaks the camel’s back – the factor that finally compels the smoker to quit, the sedentary to exercise, or the obese to radically alter their lifestyles. But it is also possible that measuring risk factors that cannot themselves be changed might merely provoke unrequited anxiety.  In a nonsmoker with normal weight, normal cholesterol, and an active lifestyle, for instance, it is hard to see what benefit might be gained by knowing the CRP is elevated. Indeed, it might cause anxiety that could not be easily allayed.  It would not be wrong to make the measurements, but (analogous to measuring genetic markers) the patient should be made aware before doing the test that there
is no specific treatment available.  And (like genetic markers) having such a risk factor on the medical record might conceivably affect insurability in the future.

A lot of research is being done to find ways of treating inflammation affecting the coronary arteries. If antibiotics, statins, or some other therapy eventually were shown to be of benefit, it would make a lot of sense to measure CRP and/or fibrinogen levels, even in patients with no other risk factors.  Measuring CRP and fibrinogen levels can be useful in many circumstances, and is likely to be far more useful in the future.  But before ordering these tests, the doctor and the patient ought to be able to say ahead of time how
the results might be useful.  Especially in patients with no other risk factors, doing these tests may cause more harm than good, and patients need to understand that before the measurements are made.

Framingham Heart Study Shows ABS Diagnostic FiF Test Has a Stronger Association With Cardiovascular Disease Risk Than Traditional Test Methods.

 Author/s: Issue: Oct 3, 2000

Fibrinogen May be the Missing Link Between Heart Disease Risk Factors

COPIAGUE, N.Y., Oct. 3 /PRNewswire/ --

American Biogenetic Sciences, Inc. (ABS) (Nasdaq: MABA) an article published in the journal Circulation: Journal of the American Heart Association found that the blood clotting protein fibrinogen seems to be a common pathway by which other risk factors cause heart disease. The study utilized American Biogenetic Sciences' patented, FDA approved, Functional Intact Fibrinogen test (FiF) in 2,632 patients in the Framingham Offspring Study -- a continuation of the famed Framingham Heart Study begun more than fifty years ago.

This study, performed by Geoffrey H. Tofler MD, and other scientists at Harvard Medical School and Boston University, demonstrated that the FiF test may be more adaptable for measuring fibrinogen levels in large populations. Indeed, "we not only found fibrinogen levels to be higher in people with heart disease but it also seems to be a common pathway by which other risk factors cause heart disease," states Tofler. Moreover, Tofler also says that the data from this study "supports the argument that measuring fibrinogen provides useful information for assessing an individual patient's risk (of developing cardiovascular disease)." The ABS FiF test demonstrated a stronger association with cardiovascular disease than did the Clauss method (the current standard in fibrinogen testing).

In the Clauss assay fibrinogen is measured indirectly as a function of clotting time. In contrast the ABS FiF assay employs a fibrinogen specific monoclonal antibody, developed using ABS' patented antigen free mouse technology, to measure directly the fibrinogen concentration. In comparing the test the authors stated the FiF test was not affected by anticoagulants or fibrin degradation products and when the tests were adjusted for covariants FiF remained significantly correlated to prevalent cardiovascular disease and the Clauss Method did not.

"We have known that our FiF diagnostic was an elegant test for measuring fibrinogen," said John S. North, President and CEO of ABS. "This study shows how important measuring fibrinogen is for the millions of patients at risk for heart attacks. We believe that based on this study the American Heart Association will add testing of fibrinogen to its recommended screening to assess cardiovascular disease risk in the general population. ABS is now in the process of finding partners to adopt the FiF test to high throughput automated laboratory systems."

"We are both happy and excited with the release and publication of these independent data from such a prestigious clinical study," states Alfred J. Roach Chairman of ABS. Roach also added, "as cardiovascular disease remains the number one cause of mortality and morbidity in developed countries, the clinical implications of these findings are extremely important for our number one priority of saving lives with the subsequent overall improvement in healthcare."