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Deep Vein Thrombosis in Pregnancy and Postpartum; Are Sulfur-Containing Amino Acids Involved in Thrombophilia Condition?

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Cristiana Filip, Catalina Filip, Roxana Covali, Mihaela Pertea, Daniela Matasariu, Gales Cristina and Demetra Gabriela Socolov

Submitted: 06 February 2024 Reviewed: 07 February 2024 Published: 09 May 2024

DOI: 10.5772/intechopen.1004607

Cysteine - New insights IntechOpen
Cysteine - New insights Edited by Nina Filip

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Cysteine - New insights [Working Title]

Dr. Nina Filip

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Abstract

Thrombophilia is a life-threatening condition causing deep vein thrombosis associated with pulmonary thromboembolism. In pregnancy and postpartum, the risk of venous thromboembolism is 5 times higher; in association with pre-existing thrombophilia becoming up to 30 times higher. The main cause of mortality at birth in underdeveloped countries is hemorrhage, while in developed countries, mortality is caused by thromboembolic complications. A peculiarity of pregnancy nowadays is the advanced age of the mother at the time of conception and assisted reproduction, both conditions presenting thrombotic risks through hyperstimulation that favors hemoconcentration as a result of high levels of estradiol generation and/or immobilization, which favors hypercoagulability and DVT respectively. In this chapter, we have summarized the most important connection between thrombophilia, deep vein thrombosis and Hcy involvement in pregnancy and postpartum conditions.

Keywords

  • cysteine
  • homocysteine
  • thrombophilia
  • pregnancy
  • deep vein thrombosis

1. Introduction

Pregnancy is characterized by physiologic changes that lead to a relative hypercoagulable state, which is accompanied by an increased stasis. The procoagulant status can be significantly amplified in the case of inherited or acquired thrombophilia, autoimmune diseases, or particular medical conditions such as prolonged immobilization. The major risk is encountered, in most cases, in the postpartum period when the incidence of venous thromboembolism increases up to 2.5 times [1]. Thus, the literature indicates a number of 500 per 100,000 venous thromboembolic events in postpartum compared to 200 per 100,000 during pregnancy [2]. In developed countries, mortality at birth is caused by thromboembolic complications compared to underdeveloped countries where the mortality is caused by hemorrhage [3]. Thus, venous thromboembolic events are very serious medical issues which have been estimated to range from 1.2 to 4.7 per 100,000 pregnancies [1]. The risk of venous thromboembolism in pregnancy is up to 30 times higher when it is associated with acquired or hereditary thrombophilia [4, 5]. During pregnancy, up to 50% of patients presenting a thrombotic event were found to have thrombophilia [1]. Currently, a new risk of venous thromboembolism has appeared for two reasons: firstly, the age of first pregnancy has moved toward 35–45 years and secondly, the number of assisted pregnancies has increased significantly. In assisted pregnancies, thrombotic risk increases due to fertilization techniques that include hormonal hyperstimulation, a procedure that promotes hypercoagulability and deep vein thrombosis (DVT). In other words, due to this combination of factors, the risk of venous thrombosis is greatly increased these days. One of the thrombogenic factors that stands out is the methylene-tetrahydrofolate reductase (MTHFR) enzyme mutation. This mutation affects the metabolism of amino acids containing the sulfur atom, namely the metabolism of methionine. As a consequence of the disruption of methionine metabolism, homocysteine (Hcy) accumulates. Homocysteine is a non-proteinogenic amino acid involved in the pathogenesis of vascular endothelium and promoter of thrombogenicity. It also represents the main precursor in Cysteine (Cys) synthesis the only proteinogenic amino acid containing a free thiol group. The structural similarity between homocysteine and cysteine makes the latter interesting to investigate for possible involvement in thrombophilia and deep vein thrombosis.

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2. Coagulation parameters during pregnancy

Physiological changes that occur during pregnancy may favor a certain level of thrombogenicity without necessarily major events (Figure 1). In contrast, postpartum thrombogenicity, which aims to avoid hemorrhage after delivery, can cause severe thrombotic events. The coagulation parameters that undergo a series of physiological changes are:

  • activated clotting factors: high levels for factors VII, VIII, X, von Willebrand factor, and fibrinogen

  • decreased anticoagulant factors: protein S level [6], adapted resistance to activated protein C

  • inhibiting fibrinolytic factors: increased activatable fibrinolytic inhibitor (TAFI), plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2).

Figure 1.

Physiological changes in the coagulation parameters during pregnancy.

When the particular condition of pregnancy overlaps with inherited or acquired thrombophilia, it is very likely that the thrombogenic effect will be significantly amplified. Inherited thrombophilia is caused either by deficiencies or by mutations of specific enzymes in the coagulation pathway. Because clotting factors are plasma-functioning enzymes, also known as zymogens, their dysfunction leads to clotting defects. Currently, three important inherited thrombophilia are considered responsible for the majority of thromboembolic events [7], namely:

  1. a mutation of the factor V gene (factor V Leiden), causes resistance to activated protein C (Figure 2). The mutation is considered the major cause of venous thrombosis and responsible for 20–30% of venous thromboembolism events [8].

  2. mutation of the prothrombin gene leads to higher concentrations of plasma prothrombin and increased risk of venous thromboembolism (Figure 2).

  3. mutation of the methylenetetrahydrofolate reductase (MTHFR) gene results in increased homocysteine plasma concentrations. The mutation causes low MTHFR activity and can be found in 5–15% of the population.

  4. Protein C (PC) is an anticoagulant serine protease synthesized by the liver that circulates in plasma as an inactive precursor. In its activated form, protein C (aPC) proteolytically inhibits the activities of coagulation factors Va and VIIIa (Figure 2). The activation of PC is triggered by the thrombin-thrombomodulin complex, located on the luminal surface of endothelial cells of blood vessels. Protein C binding to the endothelial cell Protein C receptor (EPCR) increases the efficiency of the process. Protein C activity also requires protein S as a cofactor. Once activated, protein C proteolytically degrades activated coagulation factors Va and VIIIa. Thus, within the coagulation process, activated protein C down-regulates the coagulation cascade through limited proteolytic degradation of cofactors Va and VIIIa. As a result, the amplification and progression of the coagulation cascade decrease and capillary permeability is maintained [9].

    Factor V contains three cleavage sites on which activated protein C acts. Each of these three sites contains Arg in the following positions Arg306, Arg506, and Arg 679 respectively. Following the action of aPC, factor V is proteolytically degraded, thus blocking the coagulation cascade. Dysfunctional factor V (called factor V Leiden) is caused by a point mutation in the coagulation factor V gene that substitutes Arg 506 for Gln. The presence of Glu prevents the proteolytic action of aPC, thus allowing coagulation to continue [10, 11, 12]. The literature [13] states that approximately 90% of cases with activated protein C resistance are caused by factor V gene mutation.

  5. Thrombin is a turntable in the process of coagulation, on one hand, it activates clot formation by transforming fibrinogen into fibrin, on the other hand, together with thrombomodulin, it controls the extent and intensity of coagulation.

    Thrombin is generated from prothrombin (PTM), and the prothrombin G20210A gene mutation is the second most commonly inherited thrombophilia after Factor V Leiden. The prothrombin mutation is strongly accompanied by increased levels of serum prothrombin and thromboembolic events [14, 15].

    Prothrombin is activated to thrombin mainly by factor Xa. The resulting α-thrombin molecule is composed of two chains, A and B respectively, held together by a disulfide bond formed between two cysteine residues (Cys293-Cys439). Mutations identified in this domain lead to prothrombin dysfunction [16]. Thrombin activity is controlled by antithrombin (AT), a serine protease, that inactivates thrombin. Antithrombin is synthesized by the liver, contains three disulfide bonds in its structure and a deficiency of it is associated with venous thrombosis. The literature shows that proper folding of antithrombin and the formation of disulfide bonds between the appropriate cysteine amino acids is essential for its activity [17]. The AT function is conditioned by two important structural features, namely the presence of a central loop that allows covalent binding to the active site of coagulation proteases thus inactivating them, and the presence of a structural motif (basic D-helix) that allows binding to heparan sulfate proteoglycans (HSPG) on the vascular wall [18].

  6. Mutation of the methylenetetrahydrofolate reductase (MTHFR) gene (Figure 3) results in increased homocysteine plasma concentrations largely accepted as a risk factor for both arterial occlusive disease and venous thrombosis. Homocysteine is a sulfur-containing amino acid and the higher homolog of cysteine. Unlike cysteine, which is a proteinogenic amino acid, homocysteine is a non-proteinogenic amino acid but homocysteine metabolism is a major pathway for cysteine synthesis.

Figure 2.

Inherited thrombophilia responsible for thrombogenesis.

Figure 3.

Short metabolism of sulfur-containing amino acids.

From an epidemiologic point of view, polymorphisms of the methylene tetrahydrofolate reductase (MTHFR) gene are common, literature indicates up to 40% of the general population [19]. MTHFR gene polymorphism is the main cause of hyperhomocysteinemia (HHcy), up to 20% are homozygous for MTHFR 677C > T or 1298A > C.

The risk of thrombosis and MTHFR variants is still debatable as homocysteine levels are impacted by many factors, including concomitant renal disease, thyroid disease, nutritional deficiencies, and alcohol intake.

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3. Cysteine involvement in pregnancy

Cysteine is a unique human proteinogenic amino acid that contains a reactive free sulfhydryl (–SH) or thiol group. Cysteine is crucial for protein synthesis (generates disulfide bonds in tertiary and quaternary structures), for redox homeostasis (provides the active component (-SH) in the major antioxidant agent in humans, namely glutathione), or for other metabolic functions (main component in acetyl-coenzyme A, a vital structure in energy generation). Very high doses (more than 7 grams) of cysteine may be toxic to human cells and may lead to death [20, 21]. Unlike homocysteine, which is associated with thrombogenicity, very little is known about cysteine regarding its involvement in both general and coagulation pathology. However, it is well known that a deficiency in the reabsorption of cystine (two Cys molecules linked together by a disulfide bridge) in the renal tubules can lead to stone formation and early renal failure.

The literature does not mention a direct involvement of cysteine in pregnancy or postpartum but emphasizes the effect of N-acetylcysteine (NAC) administration, in different periods of pregnancy or in the pathology encountered during pregnancy. N-acetylcysteine is a cysteine derivative in which the alpha-amino group is acetylated and the thiol group stays free. This allows the thiol group to intervene in the detoxification process as well as other processes in the body. Amin and coworkers [22] mentioned the benefit of NAC administration in recurrent pregnancy loss. The authors consider oxidative stress as the main cause that triggers a cascade of changes that may lead to pregnancy loss. As the thiol group of cysteine within NAC remains free, it is able to prevent oxidative stress by decreasing oxidative genotoxicity and by inhibiting the release of proinflammatory cytokines. Authors also find that NAC seems to mitigate the placental apoptosis and inflammatory responses that are related to severe oxidative stress. As a conclusion, authors mentioned that the use of N-acetyl cysteine in therapy enhances pregnancy outcomes in patients diagnosed with recurrent unexplained pregnancy loss (RPL) [22].

Other researchers consider that oxidative stress may be involved in the incidence of preeclampsia (PE), one of the most common pregnancy disorders [23]. N-acetyl cysteine is believed to have strong antioxidant properties and has been reported to be beneficial in preventing and treating oxidative stress in preeclampsia [24]. As a conclusion, N-acetyl cysteine supplementation is associated with a decrease in elevated blood pressure and proteinuria, which are hallmarks of preeclampsia [25].

Long-term unexplained infertility is another pathology mentioned in the literature where administration of N-acetyl cysteine appears to be beneficial. Researchers hypothesized that the effects of N-acetyl-cysteine such as: insulin-sensitizing properties, antiapoptotic and antioxidant effects, and protection against focal ischemia, may have ovulation-enhancing effects. Thus, researchers conclude that NAC is an effective, cheap, and safe adjuvant that improves pregnancy rate significantly [26, 27].

However latest data present information about oxidizing processes undertaken by cysteine and methionine (Figure 4) with thrombogenic consequences [28]. These data suggest that cysteine and methionine oxidation (Figure 4) may act as prothrombotic regulators. It seems that proteins involved in coagulation/thrombotic processes such as fibrinogen, von Willebrand factor, or β2 glycoprotein I may undertake post-translational oxidation thus promoting thrombogenesis [29, 30, 31, 32, 33].

Figure 4.

Cysteine and methionine forms oxidized under reactive oxygen species (ROS) supposed to be involved in thrombogenesis.

Moreover, a very recent study emphasizes the importance of sulfur-containing amino acids, especially cysteine. During pregnancy, free cysteine thiol groups belonging to certain proteins are converted to persulfides to generate hydrogen sulfide (H2S). Although the exact role of H2S is not yet known, it is hypothesized to be involved in stimulating vital systemic/local vasodilator processes that contribute to uterine vasodilation during pregnancy and to the regulation of vascular smooth muscle contraction/relaxation. Thus, H2S is involved in the sulfhydration of specific proteins that are responsible for regulating uterine hemodynamics [34].

To resume, the oxidation of sulfur-containing amino acids is considered a possible link between oxidative processes and thrombogenesis. On the other hand, a new role of the -SH group of cysteine in uterine hemodynamics has recently been reported.

As a conclusion, it emerges a wider involvement of cysteine in other cellular processes besides oxidative ones, which opens “new insights” in investigating the complex role of cysteine.

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4. Homocysteine and pregnancy complication

Homocysteine is an amino acid generated by the human body in the methionine metabolism. It does not participate in protein synthesis, but it is an important intermediate metabolite in major processes such as transmethylation, trans-sulfuration, cysteine formation, etc. In the transmethylation process homocysteine participates in the formation of adrenaline, melatonin, lecithin, creatine, etc. The trans-sulfuration pathway leads to cysteine synthesis, amino acid that plays a key role in the spatial conformations of protein and particularly in glutathione generation, the most important antioxidant agent in the body (Figure 3).

Homocysteine metabolism presented in Figure 3 highlights the involvement of two vitamins (folic acid and vitamin B12) and two enzymes methylene-tetrahydrofolate reductase (MTHFR) and methionine synthase (MS) respectively. The absence of these vitamins as well as the enzyme deficiencies trigger the increase of Hcy levels. The normal concentration of homocysteine in human blood is 5–15 μM. Over the past 40 years, homocysteine has been noticed in various pathologies where its concentrations exceed the above range. This condition is known as hyperhomocysteinemia (HHcy). High homocysteine concentrations are classified according to clinical consequences as being moderate at 16–30 μM, intermediary at 31–100 μM, and severe above 100 μM [35]. Nowadays it is generally accepted that HHcy promotes thrombosis [36, 37, 38].

Nowadays there are two opposite opinions regarding the role of homocysteine in pathology: first theory considers homocysteine as a risk factor [39] while the second considers Hcy as being the marker of chronic vascular injury [40]. Both points of view bring scientific arguments and, against the fact that the controversy continues, it is generally accepted that homocysteine is involved in vascular endothelial dysfunction and promotes thrombosis [41, 42, 43]. The literature mentions many diseases in which elevated homocysteine concentrations have been found in the blood: cardiovascular diseases [36, 44, 45, 46, 47, 48], neurological diseases [49, 50, 51, 52], miscarriage [53, 54, 55], thrombophilia [56, 57, 58, 59, 60, 61], bone fragility [62, 63, 64, 65, 66, 67], diabetes [68, 69, 70, 71, 72, 73, 74], inflammation [75, 76, 77].

The link between homocysteinemia and pregnancy complications is mediated by inherited/acquired MTHFR enzyme mutations (Figure 3). This mutation results in hyperhomocysteinemia, which causes thrombophilia. Miscarriage is often encountered in this condition. Clinical studies report that this mutation causes spontaneous abortions 3.3 times more frequently [53, 54]. The particular case of the simultaneous mutation of MTHFR C667T, factor V Leiden, and/or prothrombin gene mutations will definitely cause recurrent pregnancy loss [55]. In addition to the thrombogenic effect, HHcy also manifests an effect of diminishing the fibrinolytic process. Fibrinolysis is controlled by different proteins; among them, protein C plays a key role in this process. Protein C has anticoagulant activity by blocking the activity of factors V and VIII. Thus, a low level of protein C will favor the formation of clots. Data from the literature indicate that protein C activity is affected by increased levels of Hcy as a result of the formation of disulfide bridges between the two [56]. Consequently, a thrombogenic status is promoted which will favor the formation of venous and arterial clots [57, 58, 59, 60]. Therefore, a high level of homocysteine can lead to the formation of clots, deep vein thrombosis, or acute events such as pulmonary thromboembolism and also to pregnancy loss. These mechanisms are extensively presented in our previously published work [61].

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5. Homocysteine mechanism of action

The mechanisms by which hyperhomocysteinemia triggers injury processes are thought to be as follows: oxidative stress [78, 79, 80, 81, 82, 83, 84], inflammation [85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95], and cellular signaling [96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113]. High concentrations of homocysteine in the blood are considered to be harmful to vascular endothelial function.

In a physiological state, the endothelium has anticoagulant and vasorelaxant activity that favors exchanges at the cellular level. Endothelial function impairment triggers both functional (coagulability, proinflammatory cytokine secretion) and morphological (vascular hypertrophy) imbalance. As a result of injury, whatever the cause, the vascular endothelium responds through a chain of events leading to oxidative stress, intracellular signaling, and cellular renewal. The exact point or mechanism by which HHcy intercepts this chain of events has not been clearly identified. However, the generation of reactive oxygen species [75], activation of the inflammatory response [76], and cell signaling [77] are considered possible mechanisms and are widely investigated at present. Some of these scientific hypotheses will be briefly described below.

5.1 Hyperhomocysteinemia involvement in oxidative stress

Scientific evidence suggests a significant role of hyperhomocysteinemia in disrupting cellular redox balance in the vascular endothelium. The specific reactions that mediate the vascular effects of HHcy involve the synthesis of reactive oxygen species (ROS). Some of these species are themselves intracellular messengers (such as hydrogen peroxide) [78, 79, 80]. The literature highlights the fact that HHcy generates reactive species both by autooxidation and by direct reaction with other cell structures or components [81, 82]. Our studies in an experimentally induced HHcy model in rats showed that HHcy promotes the generation of hydrogen peroxide and decreases the total antioxidant capacity of serum [83, 84].

The oxidative process leads to the injury of endothelial cells [114], diminished blood vessels in villi, and decreases in pregnancy, the circulation of blood at the maternal-fetal interface. Additionally, HHcy reduces NO releasing by the endothelial cells, which affect placental perfusion [115], and induces platelet accumulation, and promotes thrombosis [116].

5.2 Hyperhomocysteinemia involvement in inflammation

Cell survival depends on responding to, eliminating, and then returning to the original, healthy structure after any type of insult or injury. To do this, cells have developed over time a complex system called the inflammasome. The inflammasome is an integrative structure that collects data about aggression, mobilizes and coordinates the response accordingly, and finally restores the initial morphological and physiological status. In addition, the inflammasome stores information about aggression to be quickly accessed in case of a future attack.

The coordination of the whole process is achieved by the activation/secretion of specific messengers of the immune system, namely cytokines [85]. Once secreted, these molecules trigger the formation of reactive species, the modification of ion fluxes, which will ultimately lead to the modulation of gene transcription in order to supply the components/proteins required for the entire process.

Recent data identify HHcy as the key factor in the formation and activation of the Nod-like receptor protein 3 complex (NLRP3) of the inflammasome [86, 87].

Current data report [88, 89] HHcy as promoting chronic inflammation in endothelial cells. Chronic inflammation is an irreversible injury, in other words, it is an incurable injury, due to its particular characteristics. This means that chronic inflammation induces abnormal morphological changes not only in the area of injury but also in the surrounding tissues, ultimately altering their normal physiology. Constantly increased levels of proinflammatory parameters such as interleukins (IL-6, IL-8, and TNFα) [90, 91] have been identified in chronic inflammation and they are positively associated with hyperhomocysteinemia. Elevated homocysteine levels stimulate IL-1beta and TNF-alpha secretion in human monocytes/macrophages. Overall hyperhomocysteinemia seems to alter the profile of cytokines produced by both endothelial cells and macrophages [92, 93, 94, 95].

5.3 Hyperhomocysteinemia involvement in cellular signaling

A causal loop is formed between inflammation and ROS, as they stimulate each other. In other words, inflammation triggers the synthesis of reactive species that act as messengers/mediators and trigger the immune system cell response. Thus, the immune cells will produce specific molecules that will act both on themselves and on other target cells. After activation and self-activation, the target cells will produce reactive species in turn. Cellular survival depends on this functional loop. In addition, inflammasome-reactive species connection functions in both pathological and physiological processes [96].

The levels of ROS concentrations make the difference between the physiological regulatory pathways and the pathological process called oxidative stress; the latter being associated with high ROS concentration [97]. Reactive species can be signals/stimuli in pathological processes, but cells can also produce them to use in intercellular signaling processes. The reactive species group includes oxygen superoxide, the hydroxyl radical, and hydrogen peroxide (H2O2). Currently, H2O2 is considered a second messenger capable of crossing the cell membrane due to its partial lipophilic character [98]. Scientific research has shown that hydrogen peroxide has similar activity to growth factors when is added to a living system. In turn, growth factors can trigger the release of hydrogen peroxide at the cellular level [99, 100, 101]. According to scientific data, ROS including H2O2 are involved in the MAPK signaling pathway that ultimately acts on gene transcription [102, 103, 104, 105, 106, 107]. HHcy generates hydrogen peroxide and, as a consequence, may indirectly intervene in the signaling process. Thus, hyperhomocysteinemia is a potential activator of the mitogenic process [108, 109, 110, 111, 112, 113].

The literature also mentions another effect of HHcy, decreased NO release that disrupts vascular relaxation and alters the anticoagulant activity of protein C [117]. Therefore, HHcy promotes endothelial injury leads to inflammation and oxidative process and finally to thrombosis [118].

As a conclusion, in a high homocysteine status, the vascular function is disturbed thus generating an increased risk of thrombosis [57, 58, 59, 60]. As a consequence, HHcy is associated with pregnancy complications.

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6. Homocysteine blood level in pregnancy

The blood Hcy concentration during normal pregnancy varies depending on the race population as seen in Table 1. M. Walker [119, 120]:

Period of pregnancy (weeks)Hcy blood concentrations (according to Walker) (mmol/L)Hcy blood concentrations (according to Y. Yang) (μmol/L)
up to 163.9–7.35.79–11.86
20–303.5–5.35.79–11.86
after 363.3–7.56.13–16.75

Table 1.

Blood Hcy concentration during normal pregnancy.

Literature mentions that pregnant women with inherited thrombophilia are more susceptible to HHCy [121, 122]. Hyperhomocysteinemia is not very common but is an important cause of deep vein thrombosis and recurrent pregnancy loss. Serum HHcy is associated with preeclampsia, recurrent miscarriage, and low birth weight for the newborn. Even so, the investigations of serum homocysteine levels are not of routine investigations, and diagnosis of this condition is missed due to an extremely rare evaluation of serum homocysteine levels. The literature mentions a case report in which an abnormally high plasma homocysteine level (26.58 μmol/L) was found following a spontaneous abortion at 28 weeks gestation. The patient had a history of two unexplained pregnancy losses without having previously been investigated for Hcy levels [123].

Langman et al. also mentioned in a retrospective case-control study that hyperhomocysteinemia is a major risk factor for venous thromboembolic disease and recurrent abortion [124].

The postpartum period is conventionally defined as 6 weeks after birth. This period is considered to have the highest risk of thrombosis. The literature mentions that the risk of postpartum thrombosis can persist up to 12 weeks after delivery [125].

However, regarding Hcy levels in the postpartum period, there are almost no data in the literature. Even so, the determination of serum Hcy levels during pregnancy is recommended because it can indicate the mother’s metabolic status and is useful in predicting the risk of adverse pregnancy and postpartum events.

Hcy is an early warning for most complications encountered during pregnancy (miscarriage, preeclampsia), but can be a warning sign for postpartum as well.

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7. Conclusion

Among sulfur-containing amino acids, homocysteine stands out because of its association with high levels of thrombosis. This association can be explained by a multifactorial mechanism, which ultimately disturbs the balance between pro-coagulation and anticoagulation factors. Coexistence of a deficiency in Hcy metabolism, such as methylenetetrahydrofolate reductase together with the mutation of some coagulation factors such as factor V Leiden and prothrombin, leads to thrombogenic risk and venous thromboembolism as well as pregnancy complications. Therefore, in addition to the investigation of coagulation parameters, we consider that blood homocysteine levels should be introduced as a routine investigation in the diagnosis of pregnant women with pregnancy complications and deep vein thrombosis.

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Conflict of interest

The authors declare no conflict of interest.

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Cristiana Filip, Catalina Filip, Roxana Covali, Mihaela Pertea, Daniela Matasariu, Gales Cristina and Demetra Gabriela Socolov

Submitted: 06 February 2024 Reviewed: 07 February 2024 Published: 09 May 2024

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