All about fibrinogen: main indicators and causes of deviations

The protein component does not have its own color and dissolves in blood serum. Fibrinogen is the basis of blood clots; it is formed in the liver; its renewal is recorded every 3 days. The amount of the element is regularly checked by laboratory diagnostics. A critical minimum or maximum amount of a component can cause serious disruptions in the functioning of the body, provoke long-term bleeding or the formation of blood clots on the inner walls of blood vessels.

Complexes with this research

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• For those at risk of COVID-19 RUB 4,510

Normal protein levels

In healthy patients, fibrinogen levels depend on age:

• adult women and men – from 2 to 4 g/l;
• newborns – from 1.25 to 3 g/l;
• pregnant women - from 6 to 7 g/l.

To determine the level, venous blood is taken. Tests are taken 12 hours after the last meal; 2 hours before the procedure, you must avoid any physical activity. The patient should not smoke 40 minutes before the appointment.

During pregnancy, the amount of fibrinogen gradually changes:

• in the first 3 months – 2.98 g/l, reduced results are associated with toxicosis;
• in the second trimester – about 3.1 g/l;
• last quarter – 4.95-6 g/l.

If the protein exceeds the specified results, then the following may occur:

• infertility;
• premature placental abruption;
• thrombosis in vessels located in the umbilical cord;
• gestosis, early miscarriage;
• frozen pregnancy, premature labor;
• thrombosis or thrombophlebitis.

To timely determine developing abnormalities, pregnant women undergo a coagulogram several times throughout the entire period. Primary samples show information about the volume of fibrinogen contained, and final samples show information about the risks of developing thrombosis and the body’s readiness for labor.

Detailed description of the study

Fibrinogen, or factor I, is a plasma protein that is produced in the liver and plays an important role in the blood clotting process (hemostasis). Through various interactions, it plays an important role in stopping bleeding.

Fibrinogen is able to dissolve in plasma and serves as a precursor to the insoluble protein fibrin. The process of converting fibrinogen into fibrin, as well as the adhesion (aggregation) of platelets, is carried out with the help of three main enzymes that regulate hemostasis - thrombin, plasmin and factor XIIIa.

As a result, a blood clot is formed, consisting of fibrin strands and an accumulation of platelets. This helps stop bleeding effectively. The fibrin clot also activates the fibrinolytic system. This maintains a balance between blood clotting and protection against blood clots.

The amount of fibrinogen in the body may vary among individuals depending on age and gender. A physiological increase in the concentration of this protein is observed in pregnant women. Its level may also increase with age.

Pathological conditions that change the fibrinogen content in the body are divided into congenital and acquired. The first group of diseases is associated with mutations in genes. Some of them lead to fibrinogen deficiency in the blood, others increase its level. The presence of single mutations in the genes encoding the formation of this protein may not have any symptoms, but increases the risk of thrombosis with unfavorable concomitant factors.

Acquired diseases in which fibrinogen concentration increases primarily include infectious or other diseases accompanied by inflammation. Among them one can also note diabetes mellitus and obesity. Injuries and burns increase fibrinogen production, which is necessary to stop bleeding. An increased content of this protein is observed during pregnancy, as well as when taking estrogen hormones.

A decrease in fibrinogen levels is caused by a violation of its formation in the liver or accelerated destruction in the blood (fibrinolysis). However, in most pathological conditions (acute and chronic inflammation, trauma, burns, surgical interventions), this indicator becomes higher than normal.

Determining the amount of fibrinogen in plasma is necessary in order to assess blood clotting ability and, if necessary, carry out treatment to normalize hemostasis.

Coagulogram

Factors of the coagulation, anticoagulant (anticoagulant) and fibrinolytic blood systems take part in the hemostasis system. A change in the functional state of one of the systems is accompanied by compensatory changes in the activity of the other. Violation of functional relationships can lead to severe pathological conditions of the body, consisting of either increased bleeding or intravascular thrombus formation. The study of the hemostatic system has the following goals:

• diagnosis of disorders in the hemostasis system;
• clarification of the admissibility of surgical intervention in case of identified disorders in the hemostasis system;
• monitoring treatment with direct and indirect anticoagulants, as well as thrombolytic therapy.

Currently, the usual practice for recognizing hemostasis disorders is heterogeneous and often varies in different clinics from performing one or two uninformative tests (prothrombin index, fibrinogen) to using an overloaded list of methods, some of which duplicate each other.
Many routine tests are outdated, of little value and inaccurate. To date, assessment of the results of prothrombin time using the prothrombin index is incomparable with global methodological approaches. Conditions for taking a coagulogram

Eating food, including juice, tea, coffee, and alcohol, is not allowed for 8 hours (preferably 12) before the test. You can drink plain water. If your doctor has prescribed a test while you are taking medications that affect blood clotting, please note this when taking the test.

List of coagulogram tests:

• Lupus anticoagulant;
• D-dimer;
• Antithrombin II;
• Thrombin time;
• APTT;
• INR (PTV, PTI);
• Fibrinogen;
• Screening for antiphospholipid syndrome.

Lupus Anticoagulant
Lupus Anticoagulant is an inhibitor of the blood anticoagulant system. Being present in the blood, it increases the coagulation activity of the hemostasis system, which adversely affects the process of implantation of the embryo, the course of the entire pregnancy, and the development of the fetus.

D-dimer (fibrin degradation product, D-dimer, Fibrin degradation fragment)

Determination of D-dimer level is a highly specific and sensitive marker of thrombus formation. However, its level also increases in pathological conditions accompanied by increased fibrinolysis: hemorrhagic complications, infections, wound healing, in the presence of rheumatoid factor in the blood, etc. However, the determination of D-dimer has important diagnostic value in the diagnosis of thrombosis. Its normal level allows, with 98% accuracy, to exclude conditions accompanied by increased thrombus formation.

Antithrombin III

AT III is determined by thrombin inhibition. AT III deficiency can be hereditary or acquired. The most common clinical manifestation of hereditary AT III deficiency is the development of deep vein thrombosis and, as a consequence, pulmonary embolism. The likelihood of developing thrombotic complications in patients with AT III deficiency increases with age.

Acquired AT III deficiency may be due to decreased synthesis, increased protein intake, or loss of protein. In all these cases, there is a parallel decrease in the concentration and activity of AT III. AT III is synthesized in the liver, so some liver diseases lead to decreased AT III levels. If, in parallel with the decrease in AT III, there is an increase in the thrombogenic properties of the vascular wall and activation of coagulation, then a further decrease in AT III is observed due to its consumption, which occurs in DIC caused by various pathologies: massive injuries, sepsis, inflammation of wounds, snake bites, complicated pregnancy, cancer, etc.

In addition, a decrease in AT III synthesis is observed during therapy with estrogens and synthetic drugs with estrogenic effects, nephrotic syndrome and gastrointestinal diseases, when the loss of protein exceeds the rate of its synthesis. In these cases, a parallel decrease in AT III and albumin is observed.

Thrombin time (TV)

Gives a general assessment of the final stage of blood coagulation. This is an indicator of the transition of fibrinogen to fibrin, the state of the anticoagulant system. Does not depend on the internal and external activation system, but depends on the concentration of fibrinogen, the presence of abnormal fibrinogen, the activity of antithrombins, the processes of polymerization and stabilization of fibrin.

In the clinic, TV determination is used to monitor heparin therapy (especially high molecular weight heparin) and fibrinolytic therapy; for the diagnosis of activation of fibrinolysis, indirect diagnosis of hypo- and dysfibrinogenemia.

Clinical and diagnostic value

TV shortening:

• hyperfibrinogenemia (more than 6 g/l);

TV extension:

• severe hypofibrinogenemia (less than 1.0 g/l), dysfibrinogenemia;
• heparin therapy with regular heparin (the test detects relatively low concentrations of the anticoagulant - from 0.05 IU/ml of blood);
• the presence of fibrin polymerization inhibitors (PDF, paraproteins, etc.);
• increase in immunoglobulins;
• use of asparaginase, streptokinase, urokinase;
• a decrease in fibrinase activity (factor XIII) does not affect thrombin time.

Activated partial thromboplastin time (APTT)
APTT evaluates the intrinsic pathway of activation of the coagulation process. The test is also called kaolin-kephalin time. It is a simple and comprehensive test, sensitive to deficiencies of all coagulation factors. But it is mainly used to evaluate factors VIII, IX, XI, XII and prekallikrein. Sensitive to excess plasma anticoagulants. Does not depend on platelet count.

This test is one of the main tests for monitoring heparin treatment. In patients receiving heparin therapy, the aPTT lengthens by 1.5–2 times, which indicates the effectiveness of treatment.

Determining the APTT allows you to finally resolve the issue of tolerance to heparin: for this purpose, the APTT is determined 1 hour before the next administration of heparin. If the APTT is prolonged by more than 2.5 times compared to the norm, an increased sensitivity to heparin is noted, its dose is reduced or the interval between injections is increased.

Clinical and diagnostic value
of test extension:

• hypocoagulation and bleeding tendency;
• hemophilia (A, B, C);
• significant deficiency of factors II, V, X, XII, fibrinogen;
• von Willebrand disease;
• heparin therapy with unfractionated heparin (the test detects low concentrations of the anticoagulant - from 0.05 IU/ml of blood);
• treatment with indirect anticoagulants;
• the presence of blood clotting inhibitors (PDF, lupus anticoagulant).

A shortened test indicates hypercoagulability and a tendency to thrombus formation;
and is also observed during normal pregnancy and taking oral contraceptives. Prothrombin (thromboplastin) time (PT)

By means of PT with calculation of the international normalized ratio (INR) and prothrombin index (PI), the external mechanism is assessed in total. Prothrombin time depends on the content of prothrombin itself - factor II, as well as factors V, VII, X and fibrinogen. Used to diagnose thromboembolic and hemorrhagic conditions, to monitor treatment with indirect anticoagulants.

Clinical and diagnostic value

Prolongation of prothrombin time (PI decreases, INR increases) - a tendency to hypocoagulation. Main reasons:

• violation of protein-synthetic function of the liver;
• vitamin K deficiency (usually due to impaired breakdown and absorption of fats in the intestines);
• treatment with indirect anticoagulants;
• deficiency of factors II, V, VII, X;
• heparin therapy with regular heparin (the test responds to relatively high concentrations of the anticoagulant - from 0.5 IU/ml of blood);
• hypo-, dysfibrinogenemia, impaired fibrin polymerization;
• the presence of clotting factor inhibitors (PDF, lupus anticoagulant);
• medications: anabolic steroids, antibiotics, acetylsalicylic acid in large doses, laxatives, methotrexate, nicotinic acid, thiazide diuretics, etc.

Shortening of prothrombin time is rare and has no independent diagnostic value. Together with a shortening of APTT, it indicates a tendency towards hypercoagulation:

• thrombosis;
• increased activity of factor VII (trauma, necrosis);
• pregnancy, childbirth;
• medications: acetylsalicylic acid in small doses, oral contraceptives, corticosteroids, vitamin K, barbiturates, antihistamines, caffeine.

Currently, recording the results of prothrombin time using the prothrombin index does not meet modern requirements.
To unambiguously interpret the results of prothrombin time measurements, regardless of the laboratory, INR is used: this method allows you to mathematically correct the difference given by thromboplastins with different sensitivities. Calculated using thromboplastin standardized to the international sensitivity index. Determination of fibrinogen content

Its concentration is determined by the time of clot formation in diluted platelet-free plasma with the addition of excess highly active thrombin (according to Clauss). Fibrinogen is synthesized in the liver, from where it enters the blood. Changes in fibrinogen concentration are observed in various diseases - primarily in disorders of the hemostasis system and acute inflammation.

An increase in the amount of fibrinogen, even within normal values, is considered a risk factor for cardiovascular diseases.

Clinical and diagnostic value
Increased concentration (tendency to hypercoagulation):

• physiological (pregnancy, menstruation);
• mild forms of hepatitis;
• kidney disease;
• acute phase reactions, myocardial infarction;
• collagenoses;
• radiation sickness;
• malignant tumors (especially lung cancer);
• estrogens, oral contraceptives.

Decreased concentration (a decrease below 0.5–1 g/l causes bleeding):

• congenital afibrinogenemia, hypo- and dysfibrinogenemia;
• severe liver damage;
• condition after bleeding, injury, burn;
• bone marrow lesions (leukemia, tumor metastases);
• activation of fibrinolysis (including drugs);
• phenobarbital, anabolic steroids, unfractionated heparin in high doses.

In DIC syndrome, changes in coagulogram tests depend on the form and stage of the process.
Antiphospholipid syndrome (APL)

This is a group of diseases caused by the presence of antibodies to phospholipids. Antiphospholipid antibodies (APL) are autoantibodies of the IgG and IgM class, capable of binding to the antigenic determinants of phospholipids (cardiolipin, phosphatidylserine, phosphatidylinositol, phosphatidylic acid, phosphatidylcholine) and phospholipid binding proteins. Binding with cardiolipin occurs with the obligatory participation of a cofactor, rg-glycoprotein I.

The reasons for the production of APL have not been established. Presumably, long-term persistence of viruses that are tropic to the vascular endothelium causes: morphological and functional changes in endothelial membrane cells with the development of hypercoagulation syndrome, stimulation of B-lymphocytes, which under certain conditions produce aPL.

APL bind to phospholipids of cell membranes, changing the conformational and metabolic structure of the cell, which leads to disruption of cell function with the development of stasis and thrombosis. Due to the fact that vessels of different sizes and different locations are affected, the range of clinical manifestations of APS is diverse - thrombosis, strokes, obstetric pathology, thrombocytopenia. The incidence of aPL in various pathological conditions is presented below.

Pathological condition/APL detection frequency, %:

• Recurrent venous thrombosis: 28–71
• Recurrent miscarriage: 25–64
• Transverse myelitis: 50
• Thrombocytopenia: 27–33
• Hemolytic anemia: 38
• Arterial thrombosis: 25–31
• Pulmonary hypertension: 20–40

The most significant manifestation of APS is obstetric pathology associated with placental decidual vasculopathy - recurrent miscarriage, antenatal fetal death (usually in the 1st and 2nd trimester), severe forms of gestosis, intrauterine growth retardation.
In the population, aPL is found in 2–4% of the population. The incidence of aPL increases in patients with autoimmune, inflammatory, infectious diseases, malignant tumors, while taking oral contraceptives, psychotropic drugs. APS can be primary (there are no signs of other autoimmune diseases) or secondary (against the background of other autoimmune diseases, most often systemic lupus erythematosus). There is also a seronegative variant of APS, characterized by the absence of aPL and lupus anticoagulant in the presence of clinical manifestations of APS. In this form, only antibodies to glycoprotein I are detected.

The main criterion for the laboratory diagnosis of APS is the presence of aPL (or antibodies to cardiolipin) and lupus anticoagulant in 2 or more studies at least 6 weeks apart.

Indications for prescribing analysis for aPL:

• Obstetric pathology (recurrent miscarriage).
• Recurrent thrombosis of various locations.
• Systemic connective tissue diseases (systemic lupus erythematosus, Sjogren's syndrome).
• Thrombocytopenia.
• False-positive reaction to syphilis using cardiolipin antigen (RW, RPR).

Indications of basic coagulation tests
Test Deficiency and/or inhibition of factors/Effects of anticoagulants
XII, XI, IX, VIII, von Willebrandt, Fletcher, Fitzgerald factors V, X VII II (prothrombin) I (fibrinogen) direct/indirect.

• Thrombin time
  - normal/normal/normal/extended/extended/extended/normal.
• APTT
  - prolonged/prolonged/normal/normal/prolonged/normal/prolonged/prolonged/prolonged.
• Prothrombin time (INR)
  - normal/extended/extended/extended/normal/extended/extended/extended.
• Fibrinogen
  - normal/normal/normal/reduced or undetectable/reduced or undetectable/normal/reduced/normal.

Note.
Prothrombin time (INR) results are inversely proportional to prothrombin index results. Outdated methods for studying hemostasis disorders and options for their replacement

Method/Disadvantages/Modern methods.

• Clotting time/Low standardization/APTT.
• Recalcification time/Low standardization/APTT.
• Plasma tolerance to heparin/Low standardization/Plasma thrombin-heparin time, determination of anti-Xa activity.
• Autocoagulation test (ACT)/Low standardization/APTT, antithrombin III activity.
• Beta-naphthol (fibrinogen B), ethanol or protamine sulfate tests / Low-informative, low-quality expression of results, often false positive / Tests for thrombinemia: quantitative determination of SFMC (soluble fibrin-monomer complexes).

Optimal complex of hemostasiological laboratory tests
Test/Hemostasis link/Diagnostic significance.

• Platelet count/Vascular platelet/Main component of platelet hemostasis.
• Von Willebrand factor (VWF)/Vascular platelet/Plasma platelet adhesion cofactor and marker of vascular wall endothelial damage.
• Prothrombin time (PT)/Procoagulant (extrinsic coagulation mechanism)/Screening test to determine the factors (fibrinogen, prothrombin, factors v, VII and X) involved in blood clotting initiated by high concentrations of tissue factor.
• APTT (aPTT)/Procoagulant (intrinsic coagulation mechanism)/Screening test to determine factors (fibrinogen, prothrombin, factors V, VIII, IX, X, XI, XII, prekallikrein and high molecular weight kininogen) involved in blood coagulation upon contact activation. A phospholipid-dependent screening test that provides insight into disorders associated with the effect of the lupus anticoagulant - VA.
• Thrombin time (TT)/Procoagulant (fibrin formation)/Screening test of the last stage of blood coagulation - reaction between thrombin and fibrinogen - anticoagulant activity of antithrombin III.
• Fibrinogen/Procoagulant (substrate)/The main substrate from which fibrin is formed under the action of thrombin.
• D-dimer/Procoagulant and fibrinolytic (activation of coagulation in vivo)/Fibrin degradation product, one of the most specific tests for the diagnosis of DIC syndrome, thrombophilia and thrombosis, a marker of thrombin formation, fibrin formation and activation of secondary fibrinolysis.
• Antithrombin III/Anticoagulant/Basic physiological anticoagulant, for which heparin is a cofactor, inactivates thrombin and active factors IX, X, XI, XII.
• Protein C / Anticoagulant / Physiological anticoagulant, in the activated state, inactivates active factors V, VII, inhibits plasminogen activator (activity manifests itself mainly in the microcirculatory bed).
• Lupus Anticoagulant (LA) Confirmatory Test/Done as part of an extended screening test to confirm the presence of LA.

It is possible that this range of studies is insufficient for patients with severe pathology of the hemostatic system, but in the case of preliminary screening and monitoring of therapy, it seems necessary and sufficient.

Blood plasma analysis for fibrinogen: reference norms and deviations

When receiving the results of any research, it is important to remember that they are not the only criterion by which the attending physician makes a diagnosis and prescribes treatment. Interpretation is carried out only by a specialist in combination with anamnesis data and the results of other tests.

Based on retail clinical studies, scientists have identified fibrinogen standards that are:

• for newborns and infants up to 1 year - 1.25-3 g/l;
• adult body (men and women) -2–4 g/l;
• 12-20 weeks of pregnancy - 2.9-5.3 g/l;
• 20-28 weeks of pregnancy - 3.0-5.7 g/l;
• 28-34 weeks of pregnancy - 3.2-5.7 g/l;
• 34-42 weeks of pregnancy -3.5-6.5 g/l.

The minimum level of plasma fibrinogen required for clot formation is 0.5 g/l. Elevated readings may indicate activity of the coagulation system or the occurrence of excessive blood clots, usually they occur with the following diseases:

• development of thrombohemorrhagic syndrome;
• obesity and development of diabetes mellitus;
• death of the heart muscle due to insufficient blood supply;
• pneumonia.

If the level is elevated, the doctor prescribes high-quality therapy to eliminate the underlying disease, as a result of which the protein will eventually drop to normal on its own. Fibrinogen can also be reduced with medications: thrombolytics, antiplatelet agents, anticoagulants; food also helps: fresh vegetables, seafood, cocoa and dark chocolate, red berries.

If fibrinogen is below normal, blood clotting slows down. Lack or complete absence of protein is a life-threatening condition that can be fatal. If there is not enough protein, the clot coagulates loosely and cannot stop the bleeding quickly enough. In the complete absence of fibrinogen, the blood does not clot at all, and any injury threatens to be fatal. The condition may be congenital or acquired as a result of one of the following diseases:

• intoxication of the body;
• thrombohemorrhagic syndrome;
• poisoning with toxic substances;
• excessive intake of Omega-3;
• hypovitaminosis of vitamins C and B12;
• taking steroid sex hormones, anabolic steroids, valproic acid.

Fibrinogen drops noticeably in vegetarians who have completely abandoned animal products, as well as when alcohol enters the bloodstream. If the level is reduced, the patient’s main task after the study is to promptly consult a doctor in order to prescribe the main treatment. Fibrinogen can be increased with medications: tranexam, etamsylate, vikasol and 6-aminohexanoic acid, and the diet can be enriched with foods that contain large amounts of protein.

Increased protein

A large amount of fibrinogen warns of a hidden inflammatory process and the danger of blood clots. Pathological deviation indicates the presence of:

• rheumatism, nephrotic syndrome;
• heart attack, infections;
• diabetes mellitus, pneumonia;
• hepatitis, DIC syndrome, tuberculosis;
• cancer, trauma, burns.

The increase in fibrinogen volume in pregnant women is explained by the physiological norm. Sometimes an unusual increase in protein is associated with age-related changes and the use of oral contraceptives. If a deviation is detected, the patient must be sent for additional diagnostics to identify the root causes of the abnormal condition.

Low protein

As the amount of fibrinogen decreases, the rate of blood clotting decreases and the risk of spontaneous bleeding increases. The root cause of the anomaly lies in congenital characteristics or individual diseases:

• due to DIC syndrome;
• congenital afibrinogenemia, hypofibrinogenemia;
• deficiency of ascorbic acid and cobalamin;
• treatment with anticoagulants;
• polycythemia, taking androgens or anabolic steroids, fish oil;
• toxicosis of pregnant women - early and late type;
• poisonous snake bites;
• liver cirrhosis;
• amniotic fluid embolism - a problem that occurs in infants.

A decrease in protein units occurs in vegetarians, during therapy with antioxidants, and moderate consumption of alcoholic beverages (with clearly adjusted dosages). When the level drops from 0.5 to 1 g/l, there is a risk of bleeding from the arteries and veins of the internal organs. The condition requires hospitalization and observation by medical personnel.

How to prepare for analysis and get results

For the study, blood is taken from a vein in the morning, on an empty stomach. It is advisable not to drink alcohol the day before or eat food at least 8 hours before taking the test, not to smoke 2 hours before and to avoid physical activity. It is not recommended to take a test for fibrinogen levels during an infectious disease, during bleeding (for women - during menstruation), or within a month after a blood transfusion.

The results of the analysis can be affected by medications - heparin, antioxidants, oral contraceptives and anabolic steroids. If it is not possible to cancel them 2-3 days before the test, be sure to notify our clinic employee. The result of the sample will be ready 1-2 days after the test.

Solution

Deviation from the norm of fibrinogen does not allow us to draw conclusions about a hidden disease. The indicators make it possible to identify increased or decreased results, but not to detect the original source of the disease. To make a correct diagnosis, the patient must undergo additional laboratory diagnostic examination. Correct identification of existing pathologies will solve the problem.

Doctors warn that ignoring the altered level of fibrinogen and refusing to undergo therapeutic procedures provokes external and internal bleeding (with reduced results) or accelerated formation of blood clots (with an increased amount).

The attending physician makes the final diagnosis and selects a treatment regimen. By seeking professional help in a timely manner, the chances of complications and consequences are significantly reduced.