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Abstract

Today cancer is the major health threat; and lot of efforts are being taken by many researchers; to fight against it. Even after these advancements in technologies, still death rate is gradually increasing, and the reason is late detection, delayed treatments and vascular complications, such as venous thromboembolic events (VTE). To overcome this; there is need of accurate and prompt investigation; which will guide during intervention with its effectiveness and feasibility, recently one of such investigations is to assess levels of D-dimer.

The review is compiled through the search of electronic media; mainly Google search, Ebscohost and Pub-med etc. During search relevant key words inserted such as, D-dimer, oral cancer, Fibrinogen, Fibrinogen-degradation product (FDP), Head-neck cancer and VTE etc.

Blood plays crucial role in many investigations; and very important in cancers. This is proved that, a degradation component of blood called D-dimer, may play important role during interventions of oral & other cancers.

Key words

Cancer, Fibrinogen, D-dimer, Intervention

Introduction

Even after many innovations; oral cancer related death toll is rising [1,2], and to overcome this problem, nowadays researchers are focussing on molecular biomarkers. Presently researchers are working on D-dimer; which shows close association with cancers with comparatively better  specificity and sensitivity [3]. 

D-dimer is the breakdown product; derived from action of plasmin; a clot degrading enzyme, and this works as primary diagnostic tool in various diseases such as; deep venous thrombosis (DVT), systemic illness and cancers. Here D stands for domain and is written as D-dimer or d-dimer [4,5]. The viscosity of blood is maintained by equilibrium between coagulation phenomena and fibrinolysis, and this coagulation cascade needs transformation of soluble plasma fibrinogen into insoluble fibrin. This mechanism is also very useful in removal of accumulated fibrin and fibrinogen, which again depends on proteolytic action of plasmin [6-8].

Fibrinogen is a basic and important component of blood, which is structurally; a heterohexameric glycoprotein. The fibrinogen is formed by two sets of tri-non-identical polypeptide chains A, B and ; which are linked to each other by disulfide bonds [9]. The A chain once split into fragments of D; they point in the direction of E fragment and after that there is formation of C domain [10].  Apart from isoform II, isoform I also is present (AE); and it may be seen in a pool of fibrinogen of 420 kDa and it constitute around 4% of total human fibrinogen [11]. There are enough studies; showing association between blood clotting proteins and their contribution in tumour metastasis. These proteins such as, fibrinogen, fibrin and their degradation products affect pathophysiology of many tumours; by participating in blood clotting, inflammation, angiogenesis and metastasis.

There is close association between cancers and inflammations, where inflammatory response is always associated with progression of tumours, which depend on host response against transformed neoplastic cells and role of secretary cytokines. These factors interfere with coagulation cascade, resulting in endothelial dysfunction, platelet activation, coagulation stimulation and formation of fibrin [12]. The transformed and moving cells release numerous cytokines such as IL-1, IL-6, IL-8, IL-13, TNF-α and transforming growth factor β (TGF-β) [13].  Factors such as IL-1β and TNF-α also stimulate endothelium to produce tissue factor (TF). Along with routine physiology; the tissue factors also contribute in activation of coagulation process and further induces mitogenic and thrombin formation which are helpful for growth and metastasis of cancers in future [14,15].  The generated thrombin improves synthesis of different components such as vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), IL-6, TGF-β, MMP-2 and TF [16,17].  This change from coarse to fine clot is due to specific binding property of Cl^-; which acts during polymerization [18].  The basic fibrinogen is inert in blood but once it is converted to fibrin it plays important role in physiologic circulating system; mainly in fibrinolysis.

This article was prepared through electronic searches in various sites, such as; Google, Ebscohost and Pub-med, where D-dimer and cancer related articles were searched for around 1 year. The key words used for search were; D-dimer, oral cancer, Fibrinogen, Fibrinogen-degradation product (FDP), Head-neck cancer and VTE etc.

Table 1. Prothrombotic action on inflammation (Wang et al. 2005)

Mechanisms/Proinflammatory factors	Impact on haemostatic system and blood coagulation process
Leukocytes	Platelet activation Release of neutrophil elastase secretion of thrombomodulin by endothelial cells. Inactivation of antithrombin.
Proteins of complement system	Increase of coagulation factors Increase of tissue factor expression
Proinflammatory cytokines	Stimulation of tissue factor production Decrease of protein S level Increase of adhesive protein expression platelet activation Increase of PAI-1 synthesis
Chemokines	Activation of aggregation and adhesion of platelets Stimulation of leucocyte influx

Discussion

There is long history of D-dimer and its association with other diseases of body; such as deep vein thrombosis and venous thrombo embolism etc. Nowadays researchers are focussing towards biological markers such as D-dimer and their role in interventions of oral and other cancers of body. So today this is essential to know in and out about D-dimer and its association with oral cancer. During transformation from fibrinogen to fibrin, there is activation at high affinity binding site of alpha C-domains, which is very important for regulating fibrinogen. Sometimes this is helpful to reduce degradation of circulating fibrinogen and confine fibrinolysis at places of fibrin deposition [19].  However, lysates of plasma clots, plasma of fibrinogen and both; are main components of fibrinogen and fibrin; capable of being discriminated by SDS-PA gel electrophoresis and presence of D-dimer in plasma explains efficacy of heparin in management of haemorrhagic situations [20]. There are many regulatory components in fibrin degradation, such as gamma-dimer and alpha-polymers, thrombin and activated factor XIII. which act upon fibrinogen to form complexes; those are subsequently lysed by plasmin to produce soluble cross-linked derivatives of fibrin [21,22].  

Earlier studies explained that, plasma D-dimer a circulating soluble fibrin polymer; i.e. thrombus precursor protein (TpP), shows remarkable levels during fibrinolytic process; which alarm for thrombo-embolic events [23-25] Weisman Z et al. (1978). According to recent studies; its role in various cancers; including oral potentially malignant and malignant disorders has been discovered as a useful marker during interventions. Leena Gharat et al. (2013) [3]. These raised levels are in proportion to advancements in grades of tumor. Koopman J et al. (1987) [26]. Cancer and cancer related disseminated intravascular coagulopathies (DIC), are useful tools for angiogenesis and metastasis. Trousseau in (1865), Billorth (1878) [27]. Number of cancers; such as colorectal and breast cancers have association between D-dimer and various parameters of colorectal cancers such as; tumour stage, metastasis and thromboembolic events and growth and progress of cancers [26-30].

To improvise quality assurance, some researchers developed a solid phase enzyme immunoassay (EIA), using monoclonal antibody (No FDP-14) in plasma. Moreover, the EIA for FDP in plasma is challenging diagnostic marker for various pathological conditions, including cancers [31].  Majority of chemotherapeutic regimes affect platelet synthesis which arise as principal dose-limiting side effect [32].  According to studies, D-dimer levels are useful factors; to predict the clinical outcome and survival of lung cancer patients.  The preoperative plasma D-dimer level is an important prognostic marker in patients with operable NSCLC [33,34]. Some other studies also highlight importance of raised D-dimer levels in operable hormone receptor-negative breast cancer; and survival of these patients [35,36]. There is detailed analysis, which revealed patients with cancer who had elevated D-dimer and elevated F 1 + 2 had the highest risk of developing VTE [37]. The D- dimer levels are not only useful in cancers, but this can also be utilized during pregnancy, where; diagnostic accuracy can be assessed for adnexal torsion (AT) in pregnant women [38]. Sometimes it needs to differentiate between other lesions such as fungal, bacterial and viral infections may also result DIC [39]. The D-dimer levels guide the dose of anticoagulant therapy in patients of previous history of venous thromboembolism (VTE) [3,40,41]. D-dimer and fibrinogen/fibrin degradation products (FDP) levels are elevated in thromboembolic disorders, and the assays for detection of D-dimer and FDP are used in many laboratories for the investigation of these disorders and its more commonly noticed with malignancies and immune systems [42-44].

This is also explained that fibrin (ogen) is a critical determinant of the metastatic potential of circulating tumour cells. The recent generation of viable mouse lines with selected deficits in key haemostatic factors has provided an opportunity to directly test this long-standing hypothesis [45].

The level of D-dimer was positively correlated with tumour load, number of metastatic sites, progression kinetics and the cytokines related to angiogenesis: serum vascular endothelial growth factor, calculated vascular endothelial growth factor load in platelets and serum interleukin-6 [46]. The role of primary VTE prophylaxis in high-risk patients, during secondary prevention of recurrent VTE, remains a continuing challenge during interventions [47,48].

Concentrations of cross-linked fibrin degradation products (XL-FDPs) in plasma, measured by enzyme-linked immunosorbent assays (ELISAs) based on monoclonal antibodies (MAbs) raised against fragment D-dimer of cross-linked fibrin, increase when patients are given fibrinolytic agents [3,49]. In 1865 Trousseau reported the association between phlegmasia alba dolens and advanced malignancy, whereas in 1935 James and Matheson reported the association of VTE with occult malignancy [41] and these understanding of potential pathways helped to determine the activated haemostatic and fibrinolytic activities during novel therapeutic targets [50]. Plasma levels of D-dimer are elevated in cancer patients and the activation of the extrinsic coagulation system and the fibrinolytic cascade within a tumour is thought to be related with growth, invasion and metastasis [46].

 According to Masatoshi Oya et al., there was synergistic association; between elevated levels of plasma D-dimers with TNM staging and prognosis after surgery. The study concludes that high level of D-dimer is associated with advanced TNM stage and is associated with short survival after surgery [51].

Summary and Conclusion

Even after advances in medical technologies, cancer is a major health threat. The reason behind this is; complicated etio-pathogenesis and deviation in age factor, which resulted in younger age involvement, earlier it was common in older age group. Today many studies are targeting at molecular levels; for early detection and management. One of such recent investigation is to assess the D-dimer levels in blood plasma. Basically D-dimer is a fragment of fibrinogen formed by action of plasmin and its active presence helps to assist growth and progress of cancer towards metastasis and ultimately determine the prognosis of patient. Further studies on D-dimer levels; with authentic data and accuracy, can act as marker and help to fight against cancers.

Acknowledgement

 My special thanks to, Dr Ruchi Sharma and Dr Neha Goyal, for helping me during preparation of this article.

Conflict of Interest

There is no conflict of interest.

Source of financial support

There is no source of funds.

References

1. Rai S MR (2012) Serum circulating immune complexes as prognostic indicators in premalignant and malignant lesions of oral cavity during and following radiotherapy. J Can Res Ther 8: 116-22. [Crossref]
2. Ken RC (2012) Challenges of the Oral Cancer Burden in India. J Cancer Epidemiol: 1-17. [Crossref]
3. Gharat L, Rathod GP, Kandalgaonkar S (2013) Quantitative estimation of Serum Fibrinogen Degradation Product levels in Oral Premalignant and Malignant lesions. J Int Oral Health 5: 65-72. [Crossref]
4. Fischbach FT, Dunning MB (2009) Manual of Laboratory and Diagnostic Tests. 8 edn. Philadelphia: Lippincott Williams and Wilkins.
5. Pagana KD, Pagana TJ (2010) Mosby’s Manual of Diagnostic and Laboratory Tests. 4 edn. St. Louis: Mosby Elsevier.
6. Gaffney P (2000) Fibrin degradation products. A review of structures found in vitro and vivo. Ann NY Acad Sci 936: 594-610. [Crossref]
7. Pizzo SV, Schwartz ML, Hill RL, McKee PA (1972) The effect of plasmin on the subunit structure of human fibrinogen. J Biol Chem 247: 636-645. [Crossref]
8. Blomback B (1996) Fibrinogen and Fibrin-proteins with complex roles in hemostasis and thrombosis. Thromb Res 83: 1-75. [Crossref]
9. Joanna Kotodziejczyk MBP (2013) The role of fibrinogen, fibrin and fibrin (ogen) degradation products (FDPS) in tumor progression. Contemp Oncol (Pozn) 17: 113-119. [Crossref]
10. Doolittle RF, Kollman JM (2006) Natively unfolded regions of the vertebrate fibrinogen molecule. Proteins 63: 391-397. [Crossref]
11. Fu Y, Weissbach L, Plant PW, Oddoux C, Cao Y, et al. (1992) Carboxy-terminal-extended variant of the human fibrinogen alpha subunit: a novel exon conferring marked homology to beta and gamma subunits. Biochemistry 31: 11968-11972. [Crossref]
12. Wang X, Wang E, Kavanagh JJ, Freedman RS (2005) Ovarian cancer, the coagulation pathway, and inflammation. J Transl Med 3: 1-20. [Crossref]
13. Morganti M, Carpi A, Nicolini A, Gorini I, Glaviano B, et al. (2002) Atherosclerosis and cancer: Common pathways on the vascular endothelium. Biomed Pharmacother 56: 317-324. [Crossref]
14. Grignani G, Mayola A (2000) Cytokines and hemostasis. Haematologica 85: 967-972. [Crossref]
15. Even Ram S, Uziely B, Cohen P, Grisaru-Granovsky S, Maoz M, et al. (1998) Thrombin receptor overexpression in malignant and physiological invasion processes. Nat Med 4: 909-914. [Crossref]
16. Palatynska-Ulatanska A M, Michalskit, Parvlicka H (2007) Trombina i fibryna w procesach angiogenezy tkanek zebowi przyzebia-Przeglad pismiennictwa. Dent Med Probl 44: 307-313.
17. Vindigni A, Di Cera E (1996) Release of fibrinopeptides by the slow and fast forms of thrombin. Biochemistry 35: 4417-4426. [Crossref]
18. Medved L, Nieuwenhuizen W (2003) Molecular mechanisms of initiation of fibrinolysis by fibrin. Thromb Haemost 89: 400-419. [Crossref]
19. PJ G. Distinction between fibrinogen and fibrin degradation products in plasma (1975) Clin Chim Acta 65: 109-115. [Crossref]
20. Dyr JE BB, Hersel B, Kornalik F (1989) Conversion of fibrinogen to fibrin induced by preferential release of fibrinopeptide B. Biochem Biophys Acta 27 990: 18-24.
21. Lane DA, Preston FE, VanRoss ME, Kakkar VV (1978) Characterization of serum fibrinogen and fibrin fragments produced during disseminated intravascular coagulation. Br J Haematol 40: 609-615. [Crossref]
22. Okholm M IL, Thorlaciusussing O, Eilersen E, Boesby S (1996) Fibrin and fibrinogen degradation products in plasma of patients with colorectal adenocarcinoma. Dis Colon Rectum 39: 1102-1106. [Crossref]
23. Schmetter BS, Lamm DL, Morales A, Bander NH, Grossman HB et al. (1997) A multicenter trial evaluation of the fibrin/fibrinogen degradation products test for detection and monitoring of bladder cancer. J Urol 158: 801-805. [Crossref]
24. Weisman Z, Williams PD, Orecoj, Murphy GP (1978) Further study of fibrinogen degradation products in bladder cancer detection. Urology 12: 659-661. [Crossref]
25. Sudhoff T, Schneider W (1992) Fibrinolytic mechanisms in tumor growth and spreading. Clin Investig 70: 631-636. [Crossref]
26. Koopman J, Haverkate F, Koppert P, Nieuwenhuizen W, Brommer EJ, et al. (1987) New enzyme immunoassay of fibrin-fibrinogen degradation products in plasma using a monoclonal antibody. J Lab Clin Med 109: 75-84. [Crossref]
27. Constantini V, Zacharski LR (1992) The role of fibrin in tumor metastasis. Cancer Metastasis Rev 11: 283-290. [Crossref]
28. Blackwell K, Haroon Z, Broodwater G, Berry D, Harris L, et al. (2000) Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status. J Clin Oncol 18: 600-608. [Crossref]
29. Kim HK, Song KS, Lee KR, Kang YH, Lee YJ, et al. (2004) Comparison of plasma D-dimer and thrombus precursor protein in patients with operable breast cancer as a potential predictor of lymph node metastasis. Blood Coagul Fibrinolysis 15: 9-13. [Crossref]
30. Ghosh M AA, Raghavan MR (1990) Clinical utility of serum fibrinogen degradation products (FDP) in the diagnostic and prognostic evaluation of oral cancer. Ann Dent 492: 11-12. [Crossref]
31. Kvolik S, Jukic M, Matijevic M, Marjanovic K, Glavas-Obrovac L (2010) An overview of coagulation disorders in cancer patients. Surg Oncol 19: e33-46. [Crossref]
32. Komurcuoglu B, Ulusoy S, Gayaf M, Cruler A, Ozden E (2011) Prognostic value of plasma D-dimer levels in lung carcinoma. Tumori 97: 743-748. [Crossref]
33. Zhang PP SJ, Wang XY, Liu XM, Li K (2013) Preoperative plasma D-dimer levels predict survival in patients with operable non-small cell lung cancer independently of venous thromboembolism. Eur J Surg Oncol 39: 951-956. [Crossref]
34. Cosmi B, Legnani C, Cini M, Guazzaloca G, Palareti G (2005) The role of D-dimer and residual venous obstruction in recurrence of venous thromboembolism after anticoagulation withdrawal in cancer patients. Haematologica 90: 713-715. [Crossref]
35. Batschauer AP, Figueiredo CP, Bueno EC, Ribeiro MA, Dusse LM, et al. (2010) D-dimer as a possible prognostic marker of operable hormone receptor-negative breast cancer. Ann Oncol 21: 1267-1272. [Crossref]
36. Ay C, Dunkler D, Pirker R, Thaler J, Quehenberger P (2012) High D-dimer levels are associated with poor prognosis in cancer patients. Haematologica 97: 1158-1164. [Crossref]
37. Ay C, Vormittag R, Dunkler D, Simanek R, Chiriac AL, et al. (2009) D-Dimer and Prothrombin Fragment 1+ 2 Predict Venous Thromboembolism in patients with Cancer: Results from the Vienna Cancer and Thrombosis Study. J Clin Oncol 27: 4124-4129. [Crossref]
38. Topçu HO, İskender CT, Ceran U, Kaymak O, Timur H, et al. (2015) Evaluation of the Diagnostic Accuracy of Serum D-Dimer Levels in Pregnant Women with Adnexal Torsion. Diagnostics 5: 1-9. [Crossref]
39. Cosmi B, Legnani C, Iorio A, Pengo V, Ghirarduzzi A, et al. (2010) Residual Venous Obstruction, alone and in Combination with D-Dimer, as a Risk Factor for Recurrence after Anticoagulation Withdrawal following a First Idiopathic Deep Vein Thrombosis in the Prolong Study. Eur J Vasc Endovasc Surg 39: 356e65. [Crossref]
40. Palareti G, Legnani C, Cosmi B, Guazzaloca G, Pancani C, et al. (2002) Risk of venous thromboembolism recurrence: high negative predictive value of D-dimer performed after oral anticoagulation is stopped. Thromb Haemost 87: 7-12. [Crossref]
41. Byrne M, O’Donnell JS, Keogan M, White B, Murphy S, et al. (2010) Long-term activation of the pro-coagulant response after neoadjuvant chemoradiation and major cancer surgery. Br J Cancer 102: 73-79. [Crossref]
42. Moresco RN, Júnior RH, Cláudio Rosa Vargas L, Mariano da Rocha Silla L (2006) Association between plasma levels of D-dimer and fibrinogen/fibrin degradation products (FDP) for exclusion of thromboembolic disorders. J Thromb Thrombolysis 21: 199-202. [Crossref]
43. Masago K, Fujita S, Mio T, Togashi Y, Kim YH, et al. (2011) Clinical significance of the ratio between the alpha 2 plasmin inhibitor–plasmin complex and the thrombin–antithrombin complex in advanced non-small cell lung cancer. Med Oncol 28: 351-356. [Crossref]
44. Osada T, Chong G, Tansik R, Hong T, Spector N, et al. (2008) The effect of anti-VEGF therapy on immature myeloid cell and dendritic cells in cancer patients. Cancer Immunol Immunother 57: 1115–1124. [Crossref]
45. Palumbo JS, Kombrinck KW, Drew AF, Grimes TS, Kiser JH, et al. (2000) Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells. Blood 96: 3302-3309. [Crossref]
46. Dirix LY, Weytjens R, Colpaert C, Benoy I, Huget P, et al. (2002) Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer. Br J Cancer 86: 389-395. [Crossref]
47. Lyman GH, Khorana AA (2009) Cancer, Clots and Consensus: New Understanding of an Old Problem. J Clin Oncol 27: 4821-4826. [Crossref]
48. Xu G, Zhang YL, Huang W (2004) Relationship between plasma D-dimer levels and clinicopathologic parameters in resectable colorectal cancer patients. World J Gastroenterol 10: 922-923. [Crossref]
49. Eisenberg PR, Jaffe AS, Stump DC, Collen D, Bovill EG (1990) Validity of Enzyme-Linked Immunosorbent Assays of Cross-Linked Fibrin Degradation Products as a Measure of Clot Lysis. Circulation 82: 1159-1168. [Crossref]
50. Shu YJ, Weng H, Bao RF, Wu XS, Ding Q (2014) Clinical and prognostic significance of preoperative plasma hyperfibrinogenemia in gallbladder cancer patients following surgical resection: a retrospective and in vitro study. BMC Cancer 14: 566. [Crossref]
51. Oya M, Akiyama Y, Okuyama T, Ishikawa H (2001) High preoperative plasma D-dimer is associated with advanced tumor stage and short survival after curative resection in patients with colorectal cancer. Jpn J clin Oncol 31: 388-394. [Crossref]