The natural anticoagulant protein S; hemostatic functions and deficiency

Abstract

Protein S (PS) is a vital endogenous anticoagulant. It plays a crucial role in regulating coagulation by acting as a cofactor for the activated protein C (APC) and tissue factor pathway inhibitor (TFPI) pathways. Additionally, it possesses direct anticoagulant properties by impeding the intrinsic tenase and prothrombinase complexes. Protein S oversees the coagulation process in both the initiation and propagation stages through these roles. The significance of protein S in regulating blood clotting can be inferred from the significant correlation between deficits in protein S and an elevated susceptibility to venous thrombosis. This is likely because activated protein C and tissue factor pathway inhibitor exhibit low efficacy as anticoagulants when no cofactors exist. The precise biochemical mechanisms underlying the roles of protein S cofactors have yet to be fully elucidated. Nevertheless, recent scientific breakthroughs have significantly enhanced comprehension findings for these functions. The diagnosis of protein S deficiency, both from a technical and genetic standpoint, is still a subject of debate due to the complex structural characteristics of the condition. This paper will provide an in-depth review of the molecular structure of protein S and its hemostatic effects. Furthermore, we shall address the insufficiency of protein S and its methods of diagnosis and treatment.

Plain Language Summary

What is the purpose of this summary?

• To provide an in-depth review of the molecular structure of protein S and its hemostatic effects.

• To address the deficiency of protein S and its methods of diagnosis and treatment.

What is known?

• Protein S operates as an anticoagulant through its roles as a cofactor for APC, TFPI, and an inhibitor of FIXa.

• Protein S deficiency can be either inherited or acquired.

What is new?

• Plasma protein S and platelet-derived protein S contribute to regulating coagulation and maintaining hemostasis. Protein S can be used as a potential promising treatment target for persons diagnosed with hemophilia.

Keywords:

• Deep vein thrombosis
• fibrinolysis
• protein C
• protein S
• pulmonary embolism

Introduction

Hemostasis is a complex and intricate physiological mechanism that limits bleeding from blood vessels in response to damage.¹ It involves the formation of blood clots to staunch bleeding and removing excess clots once the injury has healed.² The process of achieving sufficient hemostasis can be divided into multiple stages. It begins with forming the primary platelet plug, known as primary hemostasis.³ This plug is further reinforced by synthesizing fibrin from the coagulation cascade, called secondary hemostasis.⁴ Finally, any unnecessary thrombi are dissolved through fibrinolysis.⁵ The process of primary hemostasis is initiated through the interaction between platelets and the vascular wall, facilitated by adhesive proteins, resulting in the formation of the initial platelet plug.⁶ Most clotting factors in the bloodstream exist in an inactive state known as the zymogen form, and both intrinsic and extrinsic mechanisms facilitate their conversion into the active form.⁷ The conversion of fibrinogen to insoluble fibrin and its subsequent stabilization by cross-linking by activated plasma FXIII required the presence of thrombin.⁸ A precise homeostasis of several inhibitors regulates the coagulation process. The delicate balance is disrupted when there is an elevation in coagulation factors or a reduction in natural anticoagulant levels.⁹

The primary mechanisms responsible for natural anticoagulation are antithrombin (AT), tissue factor pathway inhibitor (TFPI), and the protein C (PC) pathway.¹⁰ AT is a highly effective inhibitor of serine proteases synthesized by the liver and distributed in plasma,¹¹ with a minimal quantity also present on the surface of endothelial cells¹² and platelets.¹³ This compound is a selective inhibitor of thrombin and factor Xa (FXa), effectively binding to coagulation factors, including VIIa, IXa, XIa, and XIIa, making them inactive.¹⁴ Due to the low concentration of heparin in plasma, AT activation in the plasma is limited. However, binding AT with heparin sulfate on the surface of endothelial cells promotes their activation.¹⁵ Following activation, the reticuloendothelial system eliminates the complex AT and its associated components, depleting the more rapidly forming complex.¹⁶ Furthermore, TFPI is the second endogenous antithrombotic factor found on endothelial cells and platelets, associated with lipoproteins.² This compound strongly inhibits the FXa and tissue factor-factor VIIa (TF-FVIIa) complex.¹⁷ The latest discovery reveals that protein S (PS) has been recognized as a critical cofactor for TFPI in inhibiting FXa, particularly in the presence of modest procoagulant stimuli. However, PS does not exhibit the same inhibitory effect on the TF-FVIIa complex.¹⁸ PS is distributed throughout the plasma in conjunction with the TFPI, elevating their binding affinity for FXa and enhancing their stability within the plasma.¹⁹

PC pathway is the third mechanism of spontaneous anticoagulation. The prothrombinase and tenase complexes are linked to factor VIIIa (FVIIIa) and factor Va (FVa) cofactors, respectively.²⁰ The activation of the PC in conjunction with PS has been observed to increase the inhibition of FVIIIa and FVa while simultaneously suppressing the actions of the tenase and prothrombinase complexes.²¹ It is an anticoagulant factor and vitamin K-dependent protein composed of 419 amino acids biosynthesized by the liver.²² Thrombin production via coagulation cascades steadily rises and subsequently interacts with the transmembrane protein thrombomodulin located on the endothelial surface.²³ Upon binding to thrombomodulin, activated protein C (APC) is generated and then attaches to the adjacent endothelial protein C receptor (EPCR), thereby facilitating the activation of more PC.²⁴ Following this, APC interacts with PS to create a complex known as APC-PS, which effectively inhibits the activity of FVIIIa and FVa (Figure 1).²⁵

Figure 1. Protein C and protein S activation mechanisms. on the surface of endothelial cell membrane, thrombin (FIIa) binds to the thrombomodulin (TM) to form FIIa-TM complex, which activates protein C (APC). The affinity and efficiency of protein C is significantly increased after binding to endothelial protein C receptor (EPCR) and after dissociation their anticoagulant activity is increase. APC binds to protein S (PS) as a cofactor to form APC-PS complex and suppresses the tenase and prothrombinase activity by inhibiting FVa and FVIIIa and subsequently reducing the thrombin generation and thrombus formation.

PS was discovered in 1977 in Seattle in the US, and it takes the letter (S) from this city as a new γ-carboxyglutamate (Gla) containing protein after purifying PC from bovine plasma.²⁶ It is a 73 kDa vitamin K-dependent glycoprotein circulating at 20–25 µg/ml concentration, mainly in the α platelet granules.²² The molecular structure of PS consists of several domains, including the N-terminal Gla domain, a thrombin-sensitive region (TSR), four epidermal growth factor (EGF)-like domains and a sex hormone-binding globulin (SHBG)-like region, which is composed of two laminin G-type (LG) domains (Figure 2).²⁷ These domains are crucial in PS interaction with other proteins and for other PS fundamental roles. For example, the Gla-domain is essential for the binding of PS to the negative charge phospholipid membrane, and the TSR domain stabilizes this binding and increases the stability of PS.²⁸ It is mainly synthesized and secreted by hepatocytes, endothelial cells and platelet α granules derived from the megakaryocytes.²⁹ It contains 676 amino acid precursor proteins and is circulated in the plasma in 60% bound to complement component 4 binding protein (C4BP), while the other 40% is circulated as free protein S (FPS).³⁰ The binding site of PS is located on the β-chain of C4BP, and the specific function of the PS- C4BP complex is still unknown.³¹ This review will explain the molecular aspects of protein S and the main functions in the hemostasis mechanism. Also, we will describe the deficiency features with the diagnostic and clinical management of protein S deficiency patients.

Figure 2. The molecular Structure of Protein S (PS). PS consists of several domains, including the N-terminal Gla domain, a thrombin-sensitive region (TSR), four epidermal growth factor (EGF)-like domains and a sex hormone-binding globulin (SHBG)-like region, which is composed of two laminin G-type (LG) domains. It is essential for the interaction of protein S with the other proteins.

Protein S functions

PS is a multifunctional protein involved in various physiological processes such as hemostasis, inflammation, and other cellular mechanisms.²⁹ Within the context of hemostasis, PS anticoagulant plays a crucial role in the coagulation cascade.²³ It is a cofactor for APC,³² TFPI and functions as a direct binding inhibitor for FIXa.³³

Protein S as a cofactor of activated protein C

APC is a serine protease that inhibits the synthesis of thrombin during the propagation phase of the coagulation process. It deactivates the cofactors FVa and FVIIIa, which are involved in the activity of prothrombinase and tenase, respectively.³⁴ PS functions as a cofactor for the proteolytic processes and regulation of coagulation by binding to APC.³⁵ The initiation of this process occurs when thrombin activates FV to FVa and subsequently binds with FXa to create the prothrombinase complex.³⁶ The inhibitory effect of APC on FVa is mediated by its proteolytic activity.³⁷ At the same time, the presence of PS significantly enhances the rate of proteolysis by 20 to 30 folds.³⁸ Nevertheless, the molecular processes behind the ability of PS to improve this rate are currently being investigated.³⁹ Recently, a scientist has developed a concept regarding the potential enhancement of PS to the efficacy of APC. It has been proposed that the active site of APC will undergo a relocation close to the phospholipid membrane upon binding of PS to APC.⁴⁰ Also, the ability of FXa to protect FVa from the inhibitory action of APC is removed by PS.³⁷ Both ideas suggested that the presence of PS enhances the attraction of APC toward negatively charged surfaces due to phospholipids.³⁹ The research conducted by Smirnov et al. presented a set of hypotheses, demonstrating that the coexistence of PS and FVa led to a significant enhancement in APC efficiency (Figure 3). Furthermore, the recruitment of APC to the phospholipid surface, which is necessary for the interaction with FVa, was significantly enhanced by more than 14 times in the presence of both PS and FVa.⁴¹ The findings presented in this study provide compelling evidence for the existence of the APC/PS/FVa complex and its role in inhibiting and regulating the coagulation process.⁴² Regarding FVIIIa, it is essential to note that PS is a cofactor for APC in the process of inactivating FVIIIa.³² This interaction leads to a reduction in thrombin generation and the formation of fibrin.⁴³ Additionally, it is worth mentioning that in the presence of PS and APC, there is a synergistic effect from FVa for the inactivation of FVIIIa.⁴⁴ The precise molecular mechanism behind the participation of PS in the inactivation of FVIIIa remains unclear.⁴³

Figure 3. The enhancement of activated protein C with cofactor protein S and FVa. the efficiency of APC is significantly increase in the presence of protein S and FVa together. The recruitment of APC to the phospholipid surface required for FVa and the efficiency of APC increased in the presence of both PS and FVa. The formation of APC/PS/FVa complex is crucial for the regulation of coagulation mechanisms.

Protein S as a cofactor of tissue factor Pathway Inhibitor and direct inhibitor of FIXa activity

TFPI is a glycoprotein that consists of a single chain and contains a proteinase inhibitor domain.^45,46 It is present in plasma at relatively low levels.⁴⁶ There are two isoforms, TFPIα, held in platelets and released when activated,¹⁹ and TFPIβ, linked to endothelial cells.⁴⁷ This compound directly inhibits the activity of the free FXa and the TF-FVIIa complex.⁴⁸ PS play a crucial role in modulating the coagulation cascade via the extrinsic pathway, primarily by acting as a cofactor for TFPI.⁴⁹ PS is a cofactor for the TFPIα isoform, which can be found in plasma or secreted from platelets. However, it does not influence the TFPIβ isoform.⁵⁰ The concentration of the TFPIα isoform in plasma is correlated with the concentration of PS.¹⁸ This correlation has been seen in patients with a quantitative deficiency in PS, who also exhibit a decrease in the concentration of TFPIα isoform. This connection implies a strong interaction between PS and the TFPIα isoform in plasma.⁵¹ In basic terms, the association between PS and TFPIα isoform involves the suppression of FXa. Nonetheless, the complete molecular mechanisms behind this functionality remain undiscovered.⁵²

Factor IX (FIX) is a zymogen, which is a 55-kDa single-chain polypeptide and present in the plasma at a concentration of 70–90 nM.⁵³ When FVIIIa is present, FIX is activated to FIXa and triggers the activation of FX to FXa which is crucial in the intrinsic coagulation pathway.⁵⁴ Recently, PS has been found to have an additional role by directly binding and inhibiting of FIXa, whether FVIIIa is present or not.⁵⁵ This novel function of PS is essential for the maximal regulation of thrombin generation in the presence of FIXa and FVIIIa.⁵⁶ The involvement of FIXa in this context was identified through in vivo experiments that demonstrated its direct interaction with the K132, K126, and R170 amino acid residues in the FIXa heparin-binding exosite. This interaction suppressed the intrinsic Xase complex and subsequent regulation of thrombin production.⁵⁷ Interestingly, Hemophilia B mice that were given an infusion of a FIXa double mutant, specifically K132A/R170A, which had complete functionality but was unable to bind to PS, showed a faster rate of fibrin clot formation compared to animals that were infused with the wild type FIXa. Significantly, the interruption of PS and FIXa binding resulted in an elevated rate of blood clot formation in mice with Hemophilia B.⁵⁷ These findings demonstrated that PS-FIXa interaction is a significant regulating mechanism for thrombin generation and thrombus formation.⁵⁸

Gene regulation of PS and their hemostatic regulation

PS is observed in genomic DNA, and it’s located on chromosome 3. This chromosome is comprised of a total of 15 exons and 14 introns.⁵⁹ The gene encoding PS contains specific binding sites for transcription factors, including Sp1.⁶⁰ It has been hypothesized that deregulating these binding sites may lead to aberrant upregulation of PS in individuals affected by cancer. Furthermore, the expression of PS can be regulated by many hormones, including progesterone and estrogen.⁶¹ The progesterone can promote the expression of PS by approximately 25%.⁶² However, it is downregulated by estrogen because the ER binding to promoter-distal GC-rich motifs of the PS gene is promoting.²⁹ Resulted of that RIP140 and HDA3 complexes that deacetylate histones can recruited which increase the risk of developing deep vein thrombosis (DVT) in the pregnant women.⁶³ Interleukin-6 (IL-6) is an additional regulator of PS expression throughout the inflammatory process, playing a crucial role in regulating inflammation.⁶⁴ Nevertheless, any genetic mutation can influence the expression and function of protein S.⁶⁵

As previously indicated, PS play a pivotal function in regulating the coagulation process. The presence of PS deficiency has contributed to an increased risk of developing venous thromboembolism (VTE), particularly DVT.⁶⁶ A recent study demonstrated that platelet-derived protein S, can modulate thrombus formation in condition of low-shear stress, with the involvement of APC and TFPI as cofactors. The results of this study indicated that both plasma PS and platelet-derived PS may play a role in regulating the coagulation process and maintaining hemostasis. However, the specific method by which platelet-derived PS does this function remains unclear.⁶⁷ Conversely, PS exhibits promise as a prospective therapeutic target for individuals diagnosed with hemophilia.⁶⁸ Currently, multiple target medicines for TFPI are being evaluated in clinical trials.⁶⁹ However, PS exhibits more value than TFPI therapies due to its multifunctional involvement in coagulation.⁶⁸

Protein S deficiency

PS deficiency may occur as either an inherited condition or acquired due to external factors. Hereditary PS deficiency is an uncommon yet significant autosomal dominant condition exhibiting symptoms similar to other coagulation inhibitors.⁷⁰ The predominant clinical manifestations in individuals with heterozygous PS deficiency are DVT and pulmonary embolism (PE).⁷¹ Instances of homozygous and compound heterozygous PS deficiencies are infrequently documented,⁷² and in most cases, they are linked to the development of severe purpura fulminans during the newborn stage.⁷³ The exact incidence of PS deficiency in the general population is uncertain; however, it is acknowledged to be minimal.⁷⁴

Approximately 300 mutations in PS have been found and categorized, resulting in the classification of PS deficiency into three distinct types.⁷⁵ The Type I deficiency results from modifying the Sp1 transcription factor binding within the promoter region, reducing the overall PS levels.⁷⁶ In cases of type II deficiency, mutations in the propeptide (specifically Arg40Leu and Arg40Leu) prohibit the PS from maturing. It leads to changes in the cofactor APC. However, the overall quantity of PS remains unaffected.⁷⁷ Furthermore, in cases of type III deficit, the overall amount of PS remains the same. However, FPS levels and the activity of APC are diminished.⁷⁸ One of the highly significant mutation in PS, known as PS-Tokushima, is associated with a genetic risk factor for DVT in the Japanese population.⁷⁹ In this mutation, the second PS epidermal growth factor-like (EGF) domain contained the variant p.Lys196Glu, K196E, which was overlooked.⁸⁰ The frequency of this particular variant was determined to be approximately 1.65–1.8% among the whole Japanese population.⁸¹ However, the presence of this condition has not yet been detected in the Chinese, Korean, or Caucasian populations.⁸²

PS deficiency can be acquired due to factors such as kidney illness, cancer, pregnancy, or the use of oral contraceptives containing estrogen.⁸³ Data indicates that PS deficiency contributes to increased blood clotting in these individuals.⁸⁴ Acquired PS deficiency is observed in women with elevated estrogen levels, and the underlying process is currently unknown.⁸⁵ The risk of loss recurrent pregnancy is 15-fold increases in women with PS deficiency which recommend the thrombophilia screening tests and treatment with low molecular weight heparin (LMWH).⁸⁶ In normal pregnancy, the coagulation profiles and thrombophilia markers during the three trimesters should be monitoring because it could be changed and may help doctor effectively to diagnose and treat any conditions may arise during pregnancy.⁸⁷ Furthermore, sickle cell anemia is another factor that can lead to acquired PS deficiency, increasing the patient’s susceptibility to thromboembolic diseases.⁸⁸ Moreover, hypoxia can reduce the production of PS by stabilizing the typical hypoxia response in the liver known as HIF1α, which in turn promotes the development of thrombosis.⁸⁹ Additionally, human immunodeficiency virus (HIV) infection or multiple myeloma (MM) can also cause acquired autoimmune PS deficiency.⁹⁰ The other pathological factors, such as disseminated intravascular coagulopathy (DIC) and oral anticoagulant medication, such as warfarin, are associated with acquired PS deficiency.⁹¹ The association between warfarin and acquired PS deficiency should be considered during the treatment regime of thrombosis in PS-deficient patients.⁹² Basically, warfarin is the predominant anticoagulant used for the treatment of DVT or PE.⁹³ The injectable anticoagulants such as heparin and LMWH must be administered with warfarin until it reaches its full effectiveness.⁹⁴ In patients with PS deficiency, warfarin must be use with other anticoagulant such as LMWH because warfarin alone can inhibit the production of PS and may exacerbate the current blood clots or trigger a new clots or a severe skin rash called skin necrosis.⁹²

Diagnosis and clinical management of protein S deficiency

The technical and genetic diagnosis of PS deficiency remains debatable due to its presence in two forms; free protein S (FPS) and a complex with C4BP, forming the PS-C4BPβ+ complex. The structural composition of PS adds complexity to antigenic and functional determination.⁹⁵ Moreover, there exists a significant convergence between the levels of PS in normal and heterozygous persons, and these levels tend to vary periodically. Furthermore, conventional methods for measuring unbound PS tend to have a high degree of inaccuracy.⁹⁶ A new assay that utilizes the strong binding between PS and C4BP has recently been demonstrated to be a highly accurate and trustworthy test.⁹⁷ The research indicates that there are inaccurately high measurements of FPS when the test temperatures are increased. This could be caused by a temperature-related rise in separating the PS-C4BPβ+ complex in samples lacking PS.⁹⁸

Plasma PS levels vary depending on age, gender, and inherited or acquired variables, such as hormone state or lipid metabolism.⁹⁹ PS levels, both total and free, are comparatively lower in women than in males. However, as individuals age, total PS levels tend to increase. This age-related difference is more noticeable in women due to variations in hormone levels. Age does not impact the levels of PS that are available without restriction. Significantly, patients with factor V Leiden, which disrupts PC function, may exhibit an erroneously low level of functional PS.¹⁰⁰ Several novel commercial techniques are now accessible for accurately identifying PS deficiency in factor V Leiden through the dilution of test plasma.¹⁰¹ The performance of total PS test is outstanding. However, they cannot identify PS deficit of types 2 and 3. FPS tests can be a valuable alternative despite their limited consistency. APC cofactor activity measurement could serve as an alternative biomarker of PS insufficiency, notwithstanding the high likelihood of false-positive results in these assays.¹⁰² Examining mutations in the PROS1 gene is crucial for detecting PS deficiency, which can be achieved using DNA sequencing or amplification and subsequent analysis using polymerase chain reaction (PCR) followed by gel electrophoresis.¹⁰³ Possible alternative diagnoses that can be considered in people with PS deficit involve antiphospholipid syndrome, AT deficiency, factor 5 Leiden mutation, PC deficiency, malignancy, prothrombin gene mutation, and paroxysmal nocturnal hemoglobinuria (PNH).¹⁰⁴

PS deficiency presents as thrombophilia, characterized by an imbalance of coagulation components, resulting in irregular blood clotting. This pathophysiological disruption places patients vulnerable to developing DIC, which can lead to severe conditions such as cerebrovascular damage or persistent VTE.¹⁰⁵ The management of VTE involves the use of anticoagulation medications, such as heparin either LMWH or unfractionated heparin, vitamin K antagonist (VKA) or direct oral anticoagulants (DOACs).⁹⁴ DOACs are anticoagulants used to prevent blood clot formation and it is alternative to the oral VKA (warfarin). It is classified into two primary categories depending on its method of action, which involves directly inhibiting coagulation factors. Oral direct factor Xa inhibitors include rivaroxaban, apixaban, edoxaban, and betrixaban. The second type acts as a direct inhibitor of thrombin (FIIa), such as dabigatran. The selection between the DOACs and VKA is based on the patient’s personal preference and level of efficiency. Previously, VKA was the preferred medication for treating VTE, but this has shifted with the introduction of DOACs.¹⁰⁶ Due to their proven effectiveness and favorable safety profile, DOACs are used more frequently to treat VTE. In cohort research involving individuals with hereditary thrombophilia, DOACs have demonstrated comparable efficacy to heparin/VKA. However, DOACs were associated with a higher likelihood of non-major bleeding, whereas VKA exhibited a slightly elevated risk of substantial bleeding.⁹⁴ Individuals afflicted with congenital PS deficiency often have an extended course of anticoagulation treatment until their coagulation activity is stable for at least two consecutive days. If the initial thrombotic episode is life-threatening or occurs in several atypical locations, such as brain veins, it is advisable to undergo lifelong therapy. If the thrombotic episode is caused by a significant trauma or surgery and the thrombosis is not life-threatening, it is not advisable.⁹³ Patients with PS deficiency who are exposed to thrombotic risk factors, such as air travel, surgery, pregnancy, or prolonged immobilization, should get prophylactic medication. Pregnant individuals in the initial trimester or after 36 weeks should get LMWH instead of warfarin to minimize the chances of bleeding in both the fetus and the mother.¹⁰⁷

Conclusion and future perspectives

The presence of a hypercoagulable state in individuals with a congenital deficit of PS highlights the critical role of this protein in regulating blood clotting. PS operates as an anticoagulant through its roles as a cofactor for APC, TFPI, and an inhibitor of FIXa. Hepatocytes, endothelial cells, and platelet α granules produced from megakaryocytes are the primary sources of synthesis and secretion of this substance. Progesterone can increase PS expression, whereas estrogen, pregnancy-related thrombosis, and interleukin-6 during inflammation can downregulate it. However, any genetic mutation can affect the expression and function of PS. Both plasma PS and platelet-derived PS likely contribute to regulating coagulation and maintaining hemostasis. The exhibits show potential as a promising treatment target for persons diagnosed with hemophilia. In addition, PS deficiency can be either inherited or acquired. Deep vein thrombosis and pulmonary embolism are the main clinical symptoms observed in persons with heterozygous PS deficiency. PS deficiency may be acquired due to conditions such as cancer and pregnancy. The diagnosis of PS deficiency is challenging due to the complexity in their structure. PS deficiency can be managed using the same approach as VTE, which entails the administration of anticoagulant medications.

The significant role of PS as an anticoagulant protein has been well-established in clinical practice.²² We understand that it plays a crucial role as a cofactor in two of our anticoagulant cascades by improving the activities of APC and TFPIα.¹⁰⁸ A distinct pattern is becoming evident, where PS and different forms of FV contribute to the development of beneficial interactions in the anticoagulant pathway.⁴² Based on the prior findings, further research is necessary to explore recent advancements in PS clinical research related to pregnancy and managing PS shortage. Furthermore, additional study is required to explore the potential association between COVID-19 morbidity and PS insufficiency. The precise functions of plasma and platelet PS in regulating thrombin production within and outside the platelet thrombus are yet to be established. Additional, comprehensive molecular explanations of the numerous connections associated with the diverse functions of PS are required. Additionally, they could serve as a foundation for comprehending how dynamic and flow variables influence the functional and clinical efficacy of PS as a regulator of hemostasis.

Authors contributions

S.A. Designed the review, wrote the manuscript and drew the figures, A.A.B and I.A.A. collected and drafted the relevant literature review part, and S.K.A. revised the manuscript.

All authors have read and agreed to the published version of the manuscript.

Acknowledgments

We acknowledge King Faisal Medical City for Southern Region (KFMCity), King Fahad Medical City (KFMC) and King Saud University (KSU) for their support.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

No funding for this work.