Plasma fibrinogen degradation products as the nonsurgical diagnostic tool for oral submucous fibrosis: A systematic review

Abstract

Aims and Objectives: 

Oral submucous fibrosis (OSMF) is known to be one of the most common premalignant conditions of the oral cavity. Areca nut (AN) is considered to be the disease’s primary cause, while there are other potential causes as well. However, routine clinical practice has revealed that not all people who chew AN exhibit clinical signs of OSMF, and few people are reported to have it even without chewing AN. So, there must be other factors contributing to OSMF. Plasma fibrinogen degradation products (FDPs) have recently been discovered to be an early sign of this disease, indicating a potential link between the two. This review aims to examine the studies which have been published in the literature that explain the role of plasma FDPs in contributing to OSMF.

Materials and Methods: 

An electronic search of the published literature was performed without publication year limitation in PubMed/ Medline, Scopus, Google Scholar, Web of Science, Science Direct, Embase, and Research gate databases, using mesh keywords like (‘Oral submucous fibrosis’ OR ‘Oral submucous fibrosis’) AND (‘Fibrinogen degradation products’ OR ‘Plasma fibrinogen degradation products’) AND (‘Clinical grades’ OR ‘Histological grades’) AND (‘Diagnosis’). A manual search of all related journals was also done. We also referred to the reference lists of papers. The risk of bias was evaluated with the GRADE criteria (from the Grading of Recommendations Assessment, Development, and Evaluation Working Group).

Results: 

The search revealed a total of 12 relevant studies from 1979 to 2022. Nine out of 12 studies demonstrated the definite presence of plasma FDPs in such cases.

Conclusions: 

Although the studies documented in the literature showing evidence of plasma FDPs in patients with OSMF are very few in number, their detection signifies an important clinical finding. More research is still required in this aspect to establish stronger evidence.

Introduction

Oral submucous fibrosis (OSMF) is known to be one of the most common premalignant conditions of the oral cavity, characterized by its wide involvement of the oral region, including the pharynx and oropharynx that can lead to tissue scarring, dysphagia, and trismus.^[1] The disease is considered to be of multifactorial etiology, with areca nut (AN) being the most predominant causative agent.

The deposition of abundant aberrant collagen in the submucosa, which causes tissue fibrosis, hyalinization, and degenerative alterations in the muscles, is the distinctive hallmark of OSMF.^[2] Studies have demonstrated that the ethanolic extracts present in AN, such as arecoline, arecadiene, etc., result in the proliferation of dermal fibroblasts, stimulating collagen synthesis and also making them resistant to collagen degradation, thus overall collagen deposition.^[3,4] However, it has been observed that the patients with OSMF do not always exhibit a habit of AN chewing, and also, the patients with AN chewing do not manifest with OSMF in 100% of cases.^[5] This led to a hypothesis that there must be other factors contributing to OSMF. Plasma fibrinogen degradation products (FDPs) have recently been discovered to be an early sign of this disease, indicating a potential link between the two.^[5-7]

FDPs are also termed fibrin split products. These are the products formed due to the degradation of plasma fibrinogen, an important protein playing a unique role in the coagulation cascade. In the first stage of coagulation, after any injury to a blood vessel, the clot is formed and the coagulation factor, thrombin is released. Additionally, fibrinogen is transformed into fibrin, which creates a fibrin meshwork. The clot is broken once the wound has healed by the enzyme plasminogen, which is transformed into plasmin, which divides fibrin further to produce fibrin-split products, or FDPs [Figure 1]. Particularly fragment Y and to a lesser extent fragment X are known to have anticoagulant effects among the principal FDPs X, Y, A, B, C, D, and E. Plasma FDPs are not seen in healthy persons who are generally normal.^[5] They are detected only when their levels rise above the normal value (>200 ng/mL). Elevated levels of plasmas FDPs have been associated with various clotting disorders such as disseminated intravascular coagulation (DIC), thrombolytic therapy, fibrinogenolysis, deep vein thrombosis (DVT), etc.

Figure 1:: Pathway of plasma fibrinogen degradation products formation (FDP: fibrinogen degradation products, TPA: tissue plasminogen activator)

Although plasma FDPs have been linked to OSMF, there have been relatively few studies that have shown their contribution to the etiopathogenesis of OSMF. We published a paper on the same subject in 2015 in which only nine such studies could be recorded.^[8] The aim of this review was to examine the studies which have been published in the literature that explain the role of FDPs in contributing to OSMF.

Materials and Methods

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards were followed for conducting the current study. There was no requirement to obtain any ethical approval given the nature of the review.

Focused Population, Intervention, Comparison, Outcome (PICO) question

The targeted Population, Intervention, Comparison, Outcome question was framed that we utilized for search screening. “How many studies have been reported in the literature indicating the measurable levels of plasma FDPs in patients with OSMF and what is the clinical significance of these plasma FDPs associated with OSMF?”

Population: AN chewers with OSMF

Intervention: Plasma FDP level detection

Comparison: 1. AN chewers without OSMF; 2. Control group (normal healthy individuals without any habits)

Search strategy for identification of studies [ Figure 2]

An electronic search of the published literature was performed without publication year limitation in PubMed/ Medline, Scopus, Google Scholar, Web of Science, Science Direct, Embase, and Research gate databases, using mesh keywords like (‘Oral submucous fibrosis’ OR ‘Oral submucous fibrosis’) AND (‘Fibrinogen degradation products’ OR ‘Plasma fibrinogen degradation products’) AND (‘Clinical grades’ OR ‘Histological grades’) AND (‘Diagnosis’). We also searched all related journals manually. The reference list of all articles was also checked.

Figure 2:: Search strategy following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines

Screening of studies

The current review involved three steps of screening of the studies. In the first step, the titles of the papers were reviewed by four authors (SG, HS, KTN, RLOE) independently and duplicates were removed. Then the four authors (RG, AS, HSB, MK) reviewed the selected abstracts of all the studies independently. In the final stage, the text of the selected studies was screened by all the authors separately. Full report was collected, discussed, and resolved for the cases that appeared not to fit the inclusion criteria or for which evidence was insufficient to make a clear determination.

Inclusion criteria

• Studies which include the role played by plasma FDPs in the etiopathogenesis of OSMF. The papers included were from 1979 to 2022.
• Type of studies: Clinicopathological studies.
• In studies including other oral diseases, only the OSMF group was included for data analysis.
• Cases were chosen without regard to restrictions on factors like age, gender, ethnicity, socioeconomic level, etc.
• Only English-language articles were included.

Exclusion criteria

• Studies which include the role played by plasma FDPs in the etiopathogenesis of diseases other than OSMF.
• Reviews, editorials, conference abstracts, hypothesis papers, web news, media reports, and animal studies.
• Articles published in languages other than English were eliminated, as well as duplicate, irrelevant, and incomplete data.

Risk of bias assessment and evidence synthesis

The risk of bias in the included individual studies was appraised following The Grading of Recommendations Assessment, Development, and Evaluation Working Group (GRADE) guidelines.^[9] In almost all the studies, the required information regarding the parameters used was available.

Data extraction and analysis

The data were extracted following study selection, screening, and careful inspection.

Cross-checking was done on the data, and it was collated into a table [Table 1].

Table 1:: Studies reported in the literature evaluating the presence of plasma fibrinogen degradation products in oral submucous fibrosis (December 1979–December 2022)

Table 1’s extrapolated data points included authors’ names and year of publication, type of study, groups included in the studies, category of patients in each group, number of individuals in each group, presence or absence of plasma FDPs, levels of plasma FDPs with increasing clinical grades of OSMF.

Results [Table 1]

The search revealed a total of 12 relevant studies evaluating the detection of plasma FDPs in patients with OSMF. The papers included were from 1979 to 2022. All the studies included in this research were clinicopathological. Nine out of 12 studies demonstrated the definite presence of plasma FDPs in patients with OSMF. In one study, plasma FDPs were detected in 43 out of 50 cases. One of the studies showed no significant levels of plasma FDP in cases with OSMF. While in one of the studies, plasma FDPs could be detected only in 14/30 patients with OSMF. In all studies, there was a significant rise in the plasma FDP levels with progressive clinical grades of OSMF, except in two studies. In one, the levels of plasma FDPs were decreased with increased clinical grades of OSMF. And in other, no significant association was observed. Plasma FDPs were undetectable in the groups with a habit of AN chewing without any evidence of OSMF. Only in 2 studies, 6 out of 50 and 3 out of 30 such cases showed the detectable values of plasma FDPs. In healthy, normal individuals without any deleterious habits, plasma FDP levels were negative.

Discussion

A significant rise in the plasma FDP levels with progressive clinical grades of OSMF was noted in most of the studies included in this review. Only one of the studies showed no significant levels of these products in patients with OSMF. Pathak (1979)^[5] reported a case of 25-year-old male patient with a habit of AN chewing in stage III OSMF. In a study he conducted, saliva from a patient with OSMF which was combined with plasma from two other healthy control subjects, and the mixture was then heated to 370°C. In contrast to the control group, he discovered that OSMF patients had higher levels of IgG, precipitable fibrinogen, cryoprecipitate-containing fibrinogen, and plasma FDPs.^[5]

Pathak (1984)^[5] comparing to seven healthy individuals and seven patients with OSMF, he observed that there was a detection of molecules immunologically similar to fibrinogen (MISFI) in seven patients.^[5]

Pathak (1984)^[5] documented a case of 25-year-old male with OSMF without any habit of AN/tobacco chewing in which plasma FDPs level was elevated to 800 mg/mL. Fibrin-producing factor (FPF) was also detected in the saliva of these patients, thus indicating the strong association between FPF and plasma FDPs.^[5]

Koshti and Barpande^[5] did a study using an XL-FDP kit based on the latex agglutination method. In the 35 individuals with OSMF, they discovered a statistically significant correlation between rising clinical grades and plasma FDP levels. They discovered that plasma FDP was a precursor to the deposition of fibrin. The fibrin deposited increased along with the plasma FDPs.

Wanjari et al.^[6] in their study found that in the saliva of subjects with the habit of chewing AN-developing OSMF, FPF was detected in 43 out of 50 cases with elevated plasma FDP levels, and in patients with AN chewing but no OSMF, only 6 cases demonstrated the presence of FPF in the saliva with normal plasma FDP levels. And in normal healthy individuals, neither FPF nor plasma FDP was detected. They used King’s method (1956) for the quantification of FDPs. They also observed a significant rise in the plasma FDPs with the increasing clinical grades of OSMF. Their findings demonstrate that there is a clear relationship between this FPF and an elevated fibrinogen level in OSMF.

Kiran et al.^[7] conducted a study in which there were 35 cases of AN chewers who also had OSMF, 10 patients who had AN-chewing habits but appeared to have normal oral mucosa, and 10 healthy patients without any habits (control group). It was noted that plasma FDPs were present in all of the AN chewers with OSMF. Controls and those who had a habit but no OSMF, on the other hand, did not exhibit FDP in the plasma. The levels of FDPs in the various clinical grades of OSMF, however, did not show any statistically significant correlation.

Gharat et al.^[10] compared patients with leukoplakia, OSMF, OSCC, and normal control cases in their study.

There was no discernible connection between the FDPs and premalignant lesions, including OSMF. But increased FDPs were found in OSCC.

Kadani et al.^[11] found that only 14 participants out of a total of 30 OSMF cases had elevated FDP levels. The latex agglutination slide test method utilized in their investigation, which according to other studies lacks sensitivity to detect the little rise in FDP levels and resulted in decreased sensitivity, may be the likely cause of undetectable FDP levels in some cases.

Gupta et al.^[12] in their study had 35 patients who chewed AN with OSMF, 30 subjects who chewed AN without OSMF, and 30 subjects who served as the control group. In their research, they found that while plasma FDPs could not be discovered in the subjects in the other two groups, they could be detected in all of the AN chewed with OSMF subjects. Additionally, it was found that plasma FDP levels increased along with the clinical grades of OSMF. The concept of agglutination served as the foundation for the quantification. The XLFDP reagent kit’s technique was capable of detecting FDP levels higher than 200 ng/mL.

Reshma et al.^[13] in their clinicopathological study assessed the plasma FDP levels in OSMF patients. Their subjects were split into two groups. Twenty-four OSMF subjects made up Group A, while 16 healthy people made up Group B. In every example of Group A, plasma FDPs were found, whereas none were found in Group B. With an increase in the severity of the clinical stage of OSMF, there was a statistically significant linear increase in plasma FDP levels.

Nayak et al.^[14] in their study had 30 AN chewers without OSMF, 40 cases of AN chewers with OSMF, and 30 cases of healthy people who had no habit or OSMF (Group III). It was noted that Group I had FDP levels that were >200 ng/mL, while Group III had no plasma FDP positive. Three of the 30 individuals in Group II tested positive for FDP. With increasing clinical stages, all of the cases in Group I demonstrated a statistically significant rise in plasma FDP levels.

Dayanandam et al.^[15] carried a study to assess the plasma FDP levels in OSMF. Twenty-five clinically diagnosed OSMF patients with AN-chewing behaviors, and 25 healthy controls without any harmful habits were involved in the study. When compared to healthy persons, all AN chewers with OSMF had higher plasma FDP levels.

In the majority of cases, included in this research, evidence of plasma FDPs has been demonstrated in patients with OSMF. The results might have varied due to different methods of using FDP-level detection. FDPs are considered to be an early diagnostic sign of fibrin deposition, and their elevated levels in OSMF suggest that the disease is characterized by increased fibrin deposition, strengthening the evidence that OSMF is a collagen disorder. And as the clinical grades progressed, FDP levels were also high, which causes a gradual reduction in mouth opening as a result of increased fibrin deposition in the connective tissue. Thus, it can be suggested that plasma FDPs could be used to measure the prognosis of the disease and also be useful as a nonsurgical diagnostic tool in suspected OSMF cases without necessitating a histopathological confirmation.

Plasma FDP levels in healthy individuals are below detectable levels. The plasma becomes detectable when the levels exceed 200 ng/dL. There are a few systematic conditions of the body in which an elevated level of these plasma FDPs has been detected such as glomerulosclerosis, cerebral contusion, pulmonary embolism, arterial thromboembolism, tachycardia/palpitation, tachypnea/dyspnea, hypotension, acute myocardial infarction, ventricular fibrillation, arteriosclerosis, DVT, DIC, and related effects.

Moresco et al.^[16] and Ikeda et al.^[17] demonstrated that high FDP levels could be evaluated in thromboembolic disorders.

OSMF is thought to have a complex etiology. AN is suggested to be the main causative agent for the development of OSMF. But several cases have been reported where patients with the habit of AN chewing do not develop OSMF. This raised a possibility of some other factor associated with OSMF. And, it is also demonstrated that the maximum changes in the oral mucosa of these patients are observed in the regions bathed with saliva which raises the suspicion that some other factors in the saliva of the patients may influence the disease process.

In OSMF, the body in response to inflammation produces more fibrinogen and its degradation products. Basic four factors have been found to be associated with the metabolism of fibrinogen: elevated fibrinogen levels, fibrinogen cyroprecipitability, FDPs, and FPF.^[5]

In light of these circumstances, researchers have proposed the theory that the parotid gland’s saliva contains FPF, a thrombin-like chemical that clots the fibrinous exudates produced in the mouth cavity. The body manufactures more fibrinogen and its byproducts in reaction to this clotting. The degradation products serve many purposes. The fibrinopeptides work to reduce inflammation, while FDP works to reduce the fibrin-like effects of thrombin and FPF produced during the autocatalytic reaction. Consequently, as the condition progresses, more FPF is created, which causes more FDP to be produced.^[5] The fact that these FDPs have been found in a variety of malignant illnesses and that their levels’ rise as the disease progresses suggests that they may be a crucial early marker for the diagnosis and prognostication of cancer. Plasma FDP levels can increase with the severity of the disease, since clinical Grade IV OSMF is also linked to other possibly cancerous conditions or oral carcinoma. In a study on OSCC, Gharat et al.^[10] discovered elevated plasma FDP levels correlating to the disease’s clinical stage. OSMF does not exhibit any hemorrhagic symptoms; hence, FDPs are classified as MISFI.^[5]

An extremely small sample size of the patients included in the individual studies was one of the review’s weaknesses, which called for additional studies.

Limitations of the Current Research

One of the limitations of the current review was a very small sample size of the patients included in the individual studies, necessitating the need for more research.

Conclusions

Despite the few studies that have been published in the literature that demonstrate the presence of plasma FDPs in patients with OSMF, the discovery of plasma FDPs in these individuals denotes a significant clinical finding and indicates that plasma FDPs can be used as a valuable nonsurgical tool in the early diagnosis of OSMF. To provide firmer evidence, more research is still needed in this area.

Future study recommendations

More studies on plasma FDP with a greater sample size are required in this area.

List of Abbreviations

AN: Areca nut

DIC: Disseminated intravascular coagulation

DVT: Deep vein thrombosis

FDP: Fibrinogen degradation products

FPF: Fibrin producing factor

GRADE: Grading of Recommendations Assessment, Development and Evaluation Working Group

MISFI: Molecules immunologically similar to fibrinogen

OSMF: Oral submucous fibrosis

PE: Pulmonary embolism

PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses

Acknowledgement

We acknowledge all the authors for their contribution and all other individuals who have assisted in completing this research in a direct or indirect way.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Author’s contributions

Sonia Gupta: Conceptualization, data curation, investigation, methodology, project administration, resources, validation, writing-original draft, writing review, and editing.

Harman Sandhu, Karthick Thangamani Nadar, Rosa Llisel Ocampo Escobedo: Data curation, Investigation, Methodology.

Radhika Gupta, Anitha Subbappa, Harkaran Singh Bhullar, Manjinder Kaur: Data curation, Investigation, Methodology, Validation.

Ethical policy and institutional review board statement

Not required for the current research.

Patient declaration of consent

Not required for the current research.

Data availability statement

All data is available in the tables, no other data can be shared.