New Findings on the Use of Fibrinogen in Gynecological Diseases

New Findings on the Use of Fibrinogen in Gynecological Diseases

Fibrinogen is a blood-soluble protein that is converted to insoluble fibrin by the release of the thrombin enzyme during blood clotting and plays an important role in blood coagulation. Fibrinogen is made in the liver and its blood level rises in conditions such as pregnancy and inflammation.

The prothrombin activator is formed in two ways, although in reality the two methods constantly interact with each other.

- The external pathway that begins with damage to the walls of the arteries and surrounding tissues (actually with the release of Tissue thromboplastin).

- The internal pathway begins in the blood itself. (By contact of coagulation factors XII and XI with endothelium, damaged collagen and other tissue elements outside the endothelium)


Converting prothrombin to thrombin

After the prothrombin activator is formed as a result of rupture of a blood vessel or as a result of damage to the blood activating material itself, the prothrombin activator can convert prothrombin to thrombin in the presence of sufficient amounts of calcium ions.

Thrombin is a protein enzyme with proteolytic properties.

 Thrombin, in turn, polymerizes fibrinogen molecules and converts them to fibrin fibers within 10 to 15 seconds.

Fibrinogen

Fibrinogen is a high molecular weight protein (340,000 daltons) with a concentration of 150 to 450 mg per deciliter of plasma.

 Fibrinogen is formed in the liver and as a result, in liver diseases, the concentration of fibrinogen in the bloodstream decreases.

Due to its naturally occurring large molecular size, fibrinogen only leaks into interstitial fluids in small amounts, and because it is one of the major factors in the process of blood clotting, normal intercellular fluid does not clot.

However, when capillary permeability increases exponentially, fibrinogen really leaks into the tissue fluid in sufficient quantities, allowing these fluids to clot in the same way as plasma and whole blood.

Conversion of fibrinogen to fibrin (clot formation)

Thrombin acts on fibrinogen and separates four low molecular weight peptides from each fibrinogen molecule, forming a monomerfibrin molecule that has the potential to automatically polymerize with other monomerfibrin molecules.

Therefore, a large number of monomerfibrin molecules polymerize in a matter of seconds and become long fibrin filaments. These filaments form the clot network.

In the early stages of this polymerization, monomerphine molecules are bonded together by weak non-covalent and hydrogen bonds, and the newly formed strands do not sink into each other.

As a result, the resulting clot is very weak and can be easily broken.

In the next few minutes, another trend emerges that makes Turbine fibrin very strong.

Holding the grid of the globule retains the final clot.

 This process is accomplished by the intervention of a substance called a fibrin stabilizing factor, which is naturally present in small amounts in plasma globulins but is also released from trapped platelets in the clot.

Fibrogen depletion can be seen in the following diseases:

Congenital diseases of poverty or lack of fibrinogen (hypofibrinogenemia or afibrinogenemia)

• Severe malnutrition

• Advanced stage of liver disease

• Receiving blood (in large quantities)

Elevated fibrinogen levels can also be seen in the following diseases:

• Acute infections

Diabetes mellitus

• Nephrotic diseases

• Types of cancer

• Coronary heart disease, myocardial infarction and heart attack (in general, increasing fibrinogen itself can increase the risk of cardiovascular disease.

• Inflammatory diseases (such as rheumatoid arthritis, glomerulonephritis)

• Injury and trauma

• Pregnancy

Fibrinogen and pregnancy

In general, pregnancy leads to an increase in hypercoagulable power, which can increase the risk of blood clots and embolisms such as deep vein thrombosis and pulmonary embolism.

During pregnancy and postpartum, the risk of blood clots is 4-5 times higher than in non-pregnant women.

Excessive coagulation during pregnancy is likely to protect women from bleeding during abortion or childbirth.

In Third World countries, the main cause of maternal death is still postpartum hemorrhage.

 In the United States, between 2011 and 2013, postpartum hemorrhage resulted in 11.4% of pulmonary embolism cases, which ultimately resulted in 9.2% of deaths due to pregnancy-related deaths.

The increased risk of clotting can be attributed to several factors.

Significant increase in coagulation factors during pregnancy, including: full Willebrand factor, fibrinogen, VII factor, VIII factor and X factor.

In pregnant women, both prostacyclin production (platelet aggregation inhibitor) and thromboxane (platelet aggregation and vasoconstriction production) increase, but in general there is an increase in platelet response that can lead to clot formation.

It also leads to enlargement of the uterus due to vasoconstriction and increased venous stasis.

In general, increased blood coagulation in pregnancy can be caused by:

- Increased basal thrombophilic risk (due to increased coagulation factors and platelet activity)

- Cesarean section,

- Preeclampsia, etc.

The clots usually form in the left leg, especially in the left iliac / femoral venous system.

Recently, several cases of May-Thurner syndrome have been reported during pregnancy, in which the right common iliac artery is constricted from the lower part of the left common iliac vein.

The level of fibrinogen in pregnancy can be two to three times higher in non-pregnant women.

Increased blood coagulation (especially in hereditary cases) can cause thrombosis in vascular vessels, which results in:

- Early-onset hypertensive disorders of pregnancy

- Preeclampsia

- and non-pathological decrease in fetal weight small for gestational age infants = SGA))

Fibrinogen changes in pregnancy can be seen in the following cases:

1. Amniotic fluid embolism (AFE): In fact, it is a hyperfibrinolysis process that is associated with decreased fibrinogen, five coagulation factor, and increased D-Dimer levels (1).

2- These markers can be used to diagnose the severity of pregnancy poisoning (Preeclampsia severity).

In general, platelet count decreased in patients with severe preeclampsia and increased levels of fibrinogen, LDH, and D-Dimer than in patients with mild preeclampsia (2).

3. The criterion for the severity of postpartum hemorrhage in patients with HELLP syndrome (Hemolysis, elevated liver enzymes, and low platelets) is the amount of fibrinogen in the blood.

If fibrinogen levels fall below 304 mg / dL in these individuals, the risk of postpartum hemorrhage increases by 7.4 times, which is 90.9% and 75.8% for Postpartum hemorrhage (3). ).

4 - Congenital afibrinogenemia, a rare autosomal recessive disease, increases the risk of hemorrhage, thrombosis, and adverse pregnancy outcomes. Studies show that fibrinogen levels in these patients should not be less than 100 mg / dL (4).

5- Reducing fibrinogen before childbirth significantly increases the risk of postpartum hemorrhage, but this distance is not enough to find a definite number of risks for it.

However, this may indicate that the critical point of fibrinogen in pregnant women should be higher (5).

Fibrinogen changes in other gynecological diseases:

1- The level of fibrinogen and platelet in endometriosis disease, which is actually one of the chronic inflammatory diseases, increases significantly compared to the control group and the group with ovarian cysts.

Using the CA 125 x Fibrinogen formula, the diagnostic power of endometriosis and its differentiation from non-endometriosis benign ovarian cysts can be increased.

The CA 125 marker alone with a cut-off of 30.75 has a sensitivity of 82.3% and a feature of 90.0% in endometriosis, while its combination with fibrinogen with a cut-off of 73.77 (IU * g / mL * L) has a sensitivity of 89.8% and a feature of 82.9% in endometriosis. will find.

Fibrinogen levels in women with severe endometriosis and severe pelvic adhesions are higher than those in the group with mild endometriosis or the group without pelvic adhesions and can therefore be used as a prognostic marker (6).

Another study found that fibrinogen levels and platelet-to-lymphocyte ratios in stage IV endometriosis were significantly higher than in stage III endometriosis, and that anticoagulant and anti-inflammatory therapies played an important role in the treatment of endometriosis (7). .

2. Ovarian cancer occurs in 70% of cases within 12 months of relapse, which plays an important role in the relapse and progression of the disease.

The combination of fibrinogen and the absolute value ratio of neutrophils to lymphocytes, called F-NLR, was used as a very good predictor marker for disease recurrence, and the grading method is as follows:


F-NLR = 0 low NLR and fibrinogen,

F-NLR = 1 for low NLR and high fibrinogen, or, conversely,

F-NLR = 2 for both high markers

Note 1: The criteria for reducing fibrinogen in these comparisons are numbers less than 200 mg / dL and increasing fibrinogen more than 450 mg / dL.

Note 2: F-NLR is considered to be less than 1 decrease (ie, the absolute value of neutrophils divided by the absolute value of lymphocyte count) and more than one increase.

It was observed that the higher the score, the faster the recurrence of the disease and the shorter the time.

Therefore, after the initial treatment of ovarian cancer and the calculation of this index, it helps a lot in how to monitor and manage the disease in ovarian cancer (so that in higher scores, follow-up times and referral to a doctor should be considered shorter - for example, every three to 6 months). (8).

3. In a study of the effects of olive oil, which is rich in unsaturated fatty acids and plays an important role in the Mediterranean diet, it was found that the incidence of cardiovascular disease (CVD) is greatly reduced. This effect is associated with a decrease in the level of fibrinogen in the blood as an important mediator of inflammation-coagulation (9).

4 - Today, it has been determined that fibrinogen plays an important role in the pathophysiology of tumor cell progression and its development towards metastasis in various types of cancers.

Measurement of fibrinogen levels before treatment of uterine leiomyosarcoma as a predictive marker is very good for disease prognosis.

Patients with high fibrinogen levels had a survival rate of about 25.0% over a 5-year overall survival rate, while patients with normal fibrinogen levels reached 52.9%.

Therefore, high levels of fibrinogen are highly associated with tumor cell invasion and poor uterine fibrosarcoma prognosis (10).

5- In general, CVD biomarkers or cardiovascular disease are:

- Total Cholestrol

- LDL, HDL

- Triglycerides,

- hs-CRP,

- Fibrinogen (11).

References:

1- Schröder L, Hellmund A, Gembruch U, Merz WM. Arch Gynecol Obstet. 2020 Apr; 301 (4): 923-929. doi: 10.1007 / s00404-020-05466-w. Epub 2020 Mar 9.

2- Duan Z, Li C, Leung WT, Wu J, Wang M, Ying C, Wang L. Dis Markers. 2020 Jan 13; 2020: 7815214. doi: 10.1155 / 2020/7815214. eCollection 2020.

3- Cui C, Ma S, Qiao R. Clin Appl Thromb Hemost. 2020 Jan-Dec; 26: 1076029619894057. doi: 10.1177 / 1076029619894057.

4- Saes JL, Laros-van Gorkom BAP, Coppens M, Schols SEM. Res Pract Thromb Haemost. 2020 Jan 22; 4 (2): 343-346. doi: 10.1002 / rth2.12300. eCollection 2020 Feb.

5- Dodge LE, Carterson AJ, Hacker MR, Golen TH, Pratt SD, Sudhof L, Collier YA, Astatke R, Uhl L. J J Matern Fetal Neonatal Med. 2019 Nov 17: 1-5. doi: 10.1080 / 14767058.2019.1688296.

6- Ding S, Lin Q, Zhu T, Li T, Zhu L, Wang J, Zhang X. BMC Womens Health. 2019 Dec 30; 19 (1): 169. doi: 10.1186 / s12905-019-0860-9.

7- Lin Q, Ding SJ, Zhu TH, Li TT, Huang XF, Zhang XM. Zhonghua Fu Chan Ke Za Zhi. 2018 Mar 25; 53 (3): 167-171. doi: 10.3760 / cma.j.issn.0529-567X.2018.03.005.

8- Marchetti C, Romito A, Musella A, Santo G, Palaia I, Perniola G, Di Donato V, Muzii L, Benedetti Panici P. Int J Gynecol Cancer. 2018 Jun; 28 (5): 939-944. doi: 10.1097 / IGC.0000000000001233.

9- Kouli GM, Panagiotakos DB, Kyrou I, Magriplis E, Georgousopoulou EN, Chrysohoou C, Tsigos C, Tousoulis D, Pitsavos C. Eur J Nutr. 2019 Feb; 58 (1): 131-138. doi: 10.1007 / s00394-017-1577-x. Epub 2017 Nov 9.

10- Bekos C, Grimm C, Brodowicz T, Petru E, Hefler L, Reimer D, Koch H, Reinthaller A, Polterauer S, Polterauer M. Sci Rep. 2017 Nov 3; 7 (1): 14474. doi: 10.1038 / s41598-017-13934-8.

11- Johnson CY, Tanz LJ, Lawson CC, Schernhammer ES, Vetter C, Rich-Edwards JW. Am J Ind Med. 2020 Mar; 63 (3): 240-248. doi: 10.1002 / ajim.23079. Epub 2019 Dec 11.
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