PERIORALNI I SUBLINGVALNI HEMATOM-KOMPLIKACIJA ORALNE ANTIKOAGULANTNE TERAPIJE-PRIKAZ SLUČAJA PERIORAL AND SUBLINGUAL HEMATOMA – ORAL ANTICOAGULATION THERAPY COMPLICATION – CASE STUDY

1 KLINIKA ZA STOMATOLOGIJU, ODELJENJE ZA ORALNU HIRURGIJU, NIŠ, SRBIJA 2 UNIVERZITET U NIŠU, MEDICINSKI FAKULTET, NIŠ, SRBIJA 3 INSTITUT ZA JAVNO ZDRAVLJE NIŠ, SRBIJA 4 CENTAR ZA PATOLOGIJU I PATOLOŠKU ANATOMIJU, NIŠ, SRBIJA 5 KLINIKA ZA STOMATOLOGIJU, ODELJENJE ZA BOLESTI ZUBA I ENDODONCIJU, NIŠ, SRBIJA 6 KLINIKA ZA STOMATOLOGIJU, ODELJENJE ZA ORTOPEDIJU VILICA, NIŠ, SRBIJA 7 KLINIKA ZA STOMATOLOGIJU, ODELJENJE ZA MAKSILOFACIJALNU HIRURGIJU, NIŠ, SRBIJA 8 UNIVERZITET U NIŠU, MEDICINSKI FAKULTET, STUDENT DOKTORSKIH STUDIJA


Introduction. Anticoagulation therapy includes drugs which prevent intravascular formation and spreading of a thrombus. Heparin and dicoumarin preparation are in use.
Heparin preparations are commonly used when a rapid anticoagulant effect is required, they are administered intravenously, act immediately performing the inhibition of thromboplastin activation, prothrombin to thrombin conversion, and the effect of thrombin to fibrinogen.Oral anticoagulation therapy (OAT) includes drugs -antagonists of vitamin K, which is responsible for the synthesis of prothrombin complex factors -II, VII, IX and X.They are derived from coumarin and indandione.One of the most frequently used drugs from the OAT group is warfarin.It is a competitive inhibitor of vitamin K required for the carboxylation of the residues of PK factor glutamic acid.The results of this inhibition lead to the unsuccessful formation of gama carboxyglutamic acid and the production of functionally inert coagulation proteins.The aim of this study was to show a rare but dangerous complication of an inadequate application of oral anticoagulation therapy.Case study.Patient S.S., male, aged 79, was admitted to the Oral Surgery Department, Clinic of Dentistry of the Faculty of Medicine in Niš on October 5, 2012 due to a severe general condition with massive hematoma in the facial area.Anamnestic data showed that during the previous couple of days, the patient was voluntarily taking a whole tablet of Farin instead of the prescribed dose.The patient started receiving intravenous low-molecular-weight heparin therapy (Fraxarin 0.3/12h) along with the antibiotic therapy.In the following period, the patient reported daily at the Oral Surgery Department for regular check-ups.The hematoma was absorbed and the swelling was completely gone within the next 7 to 10 days.

Introduction
The incidence of cardiovascular patients in general population is large, which makes this group of patients a significant category in terms of morbidity and mortality.A number of these patients has built-in artificial heart valves which creates the risk of the development of thromboembolic complications, and as such, they receive a lifelong oral anticoagulation therapy 1,2 .
Anticoagulation therapy includes drugs which prevent intravascular formation and spreading of a thrombus.Heparin and dicoumarin preparation are in use 3,4 .1. Heparin preparations are commonly used when a rapid anticoagulant effect is required, they are administered intravenously, act immediately performing the inhibition of thromboplastin activation, prothrombin to thrombin conversion and the effect of thrombin to fibrinogen.Due to intravenous administration, they are given several times a day.They are indicated as initial therapy using dicoumarol preparations which are used per os.Furthermore, they are used for the prophylaxis of deep veins thrombosis, in acute arterial thrombosis and unstable angina pectoris.2. Oral anticoagulation therapy (OAT) includes drugs -antagonists of vitamin K, which is responsible for the synthesis of prothrombin complex factors -II, VII, IX, and X.They are derived from coumarin and indandione (rarely applicable).The most commonly used are acenocoumarol (Sintrom -Novartis Switzerland), phenprocoumon (Marcumar, Marcoumar, Falithrom), ethyl biscoumacetate (Pelentan, Tromexan), warfarin (Farin -Galenika Serbia, Marivarin -Krka Slovenia) 5,6 .These were described in the professional circles in the early seventies of the twentieth century 7 .They do not affect the circulating factors of coagulation, therefore the latent period is 4 days, whereas the onset of their action is after 12 to 16 hours.This is the reason why heparin is used as initial therapy, while OAT is introduced the next day.The OAT indication area is the prophylaxis of venous thrombosis, absolute arrhythmia, artificial heart valves, acute myocardial infarction, etc.In order to control the level of OAT in the blood, a standardised INR test is used to accurately determine the optimal level for each patient.Therapy dosages depend on the type of disease: for venous prophylaxis they range from 1.5 to 2.5, for arterial prophylaxis from 2.5 to 4.5, and for artificial heart valves from Jedan od najčešće korišćenih lekova iz grupe OAT je varfarin.On je kompetitivni inhibitor vitamina K koji je potreban za karboksilaciju ostataka glutaminske kiseline faktora PK.Rezultati ove inhibicije vode neuspešnom formiranju gama karboksiglutaminske kiseline i produkciji funkcionalno inertnih koagulacionih proteina 9 .
1. 3.0 to 5.0 8 .One of the most frequently used drugs from the OAT group is warfarin.It is a competitive inhibitor of vitamin K required for the carboxylation of the residues of PK factor glutamic acid.The results of this inhibition lead to the unsuccessful formation of gama carboxyglutamic acid and the production of functionally inert coagulation proteins 9 .
Cij rada bio je da se prikaže retka, ali opasna komplikacija neadekvatne primene oralne antikoagulantne terapije.Furthermore, there is a new generation of oral anticoagulants Bayer Xarelto® (Rivaroxaban), which, according to the manufacturer, does not require coagulation control.It is the first available highly selective inhibitor of Xa factor.It has good absorption from the intestines and thus manifests its maximal effect four hours after the received therapy.The effects last for 8 to 12 hours, however, Xa factor restarts its activity within 24 hours.
One of the rare but possible complications of OAT is overdosing given that such patients are under constant supervision of cardiologists and transfusiologists.The risk of haemorrhage increases with OAT being more intensive 10 .
The aim of this study was to show a rare but dangerous complication of an inadequate application of oral anticoagulation therapy.
After examining medical records, it was found that the patient suffered from angina pectoris, diabetes mellitus, hypertension, absolute arrhythmia, cicatrix myocardii par.inferioris and hyperlipidemia, and that he was receiving continuous therapy (Monizol, Lorist, Lopion, Tensec, Cornelin, Limeral, Glucophage, Lasix, Spironolacton and Nytroglicerin).It was also found that he was on OAT with Farin, with a prescribed dose of ¼ tablet a day with regular check-ups, to which, according to his own admission, he had never been.Anamnestic data showed that during the previous couple of days, the patient was voluntarily taking a whole tablet of Farin instead of the prescribed dose.During the night, he hurt the cheek mucosa on the right side, due to which he felt slight pain, but there was no bleeding.In the morning, he noticed a swelling and a hematoma on the right cheek, which increased in size throughout the day.Kliničkim pregledom je ustanovljen otok i hematom desne strane lica koji se prostirao od donje ivice zigomatične kosti do donje ivice mandibule i od prednje ivice musculus masetera do ugla usana, zahvatajući i predeo donje i gornje usne sa te strane.Otok je bio tamnoljubičaste boje palpatorno elastičan, čvrst i bezbolan.Intraoralno se hematom prostirao od ugla usana do retromolarnog i parafaringealnog predela desne strane i od forniksa gornje vilice do poda usta u oba sublingvalna predela.Sublingvalne plike su bile edematozne, izdignute preko incizalnih ivica donjih zuba i tamnocrvene boje.Jezik je bio potisnut na gore i prema distalnim partijama usne duplje, ometajući disajni put i govor (slika 3,4).Zatvaranje i otvaranje usta kao i lateralne kretnje mandibule su bile blago ograničene.Uočen je i dekubitis sluzokože obraza u regiji prvog donjeg desnog molara (slika 5), kao i parcijalna krezubost sa neravnim i oštrim ivicama prisutnih zuba (slika 6).Slika 3. Sublingvalni hematom -prednji pod usta Figure 3. Sublingual hematoma -anterior floor of the mouth When breathing and swallowing became difficult, the patient saw a doctor at the Oral Surgery Department, Dentistry Clinic of the Faculty of Medicine in Niš for the appropriate therapy.
The clinical examination showed swelling and hematoma of the right side of the face, spreading from the lower edge of zygomatic bone to the lower edge of the mandible, and from the front edge of musculus masseter to the corner of the lips, including the area of the upper and lower lip on that side.The swelling was dark purple in colour, elastic to touch, hard and painless.Intraorally, the hematoma stretched from the corner of the lips to the retromolar and parapharyngeal area of the right side, and from the upper jaw fornix to the mouth floor, in both sublingual regions.The sublingual folds were edematous, raised over the incisal edges of lower teeth, dark red in colour.The tongue was pushed upwards and towards the distal parts of the oral cavity, obstructing the airway and speech (Figure 3, 4).Closing and opening of the mouth, as well as lateral mandibular movements, were slightly limited.In addition, cheek mucosa decubitus was noticed in the lower right first molar region (Figure 5), as well as partial edentulism with uneven and sharp edges of the existing teeth (Figure 6).In addition, cheek mucosa decubitus was noticed in the lower right first molar region (Figure 5), as well as partial edentulism with uneven and sharp edges of the existing teeth ( Figure 6 ).Nakon obavljenog kliničkog pregleda, bolesnik je smešten na Odeljenju intenzivne nege, gde mu je ordinirana antibiotska terapija: amp.Nilacef 1.5 g/12 h; Sol.Orvagil 400 mg/8h.Hitno je urađena kompletna krvna slika, laboratorija i skrining test koagulacije.S obziron na to da je bio u pitanju srčani bolesnik, pregledan je od strane kardiologa.
After the clinical examination had been done, the patient was placed in the intensive care unit where he received antibiotic therapy: amp.Nilacef 1.5g/12h; Sol.Orvagil 400mg/8h.An urgent complete blood count, laboratory and coagulation screening test were done.Since the patient was a heart patient, he was also examined by a cardiologist.
The patient immediately received fresh frozen plasma and his therapy with Farin was cancelled.As his general condition was stabilized, a detailed examination of the cause of decubitus was performed, as well as the conservative tooth repair to avoid further injuries.The following day the patient's results were better (INR 3.2).The patient started receiving intravenous low-molecularweight heparin therapy (Fraxarin 0.3/12h) along with the antibiotic therapy.The swelling was slowly receding.The results were even more stable on the third day.The value of INR amounted to 2.6, which was within the therapeutic range considering his disease.On the fourth day, the intravenous Fraxarin therapy was cancelled and the patient was again receiving OAT with Farin.With the general condition being stable and the hematoma in the regression phase, the patient was discharged from hospital for home treatment (Th: tbl.Clindamycin 600mg/12h).
In the following period, the patient reported daily at the Oral Surgery Department for regular check-ups.The hematoma was absorbed and the swelling was completely gone within the following 7 to 10 days.

Discussion
There were numerous controversies in the past related to dental procedures in patients receiving OAT.The largest number of haemorrhagic complications in such patients appeared prior to the standardization of oral anticoagulant control, that is, prior to the development and introduction of INR in 1983 11,3 .Attitudes that prior to tooth extraction and especially prior to oral surgical interventions OAT must be suspended or reduced to decrease the risk of haemorrhage, prevailed.Such attitudes were justified by the appearance of profuse bleeding after tooth extraction in several patients receiving dicoumarol therapy 12 .
In 1985, Ogiuchi et al. reported that temporarily cancelled OAT bears an increased risk of thromboembolism, especially in patients with artificial valves 13 .In 1998, Wahl presented several cases of severe embolic complications in patients with revoked anticoagulant therapy prior to a surgical intervention.The British Committee for Standards in Haematology, in their practical guidelines for the treatment of patients receiving OAT and requiring necessary dental procedures, state that the risk of significant bleeding in patients receiving OAT with INR is very small in the therapeutic range, whereas the risk of thrombosis increases in temporarily cancelled OAT 14 .
A prospective, randomized study carried out in Spain showed that after a surgical intervention there were no differences in the incidence of haemorrhagic complications in patients with a preoperatively reduced dose and the ones with a therapeutic Do sličnih rezultata je došao i Đovani sa saradnicima kod koga su bolesnici i u kontrolnoj i u studijskoj grupi bili bez krvarenja u periodu praćenja, u prvih 30 minuta nakon ekstrakcije zuba, kao i u prva 24 sata 16 .
Moreover, meta-analysis was done on 774 patients on continuous therapy with Farin, with INR less than 4, on whom 2014 dental procedures were performed in which 98% of the patients exhibited no serious bleeding 5 .
Nowadays, it is considered that due to crucial significance for cardiovascular patients, OAT should not be suspended for tooth extraction and smaller oral surgical interventions, and this approach is in accordance with the doctrinal approach of the Clinic of Dentistry in Niš.Regular laboratory control tests are necessary to keep the INR value in the therapeutic range.For more serious surgical interventions, OAT is suspended 24 to 48 hours prior to the intervention and the intravenous administration of low-molecule-weight heparin (fraxarin) is simultaneously introduced.After 4 to 5 days, there is an overlapping with oral coagulants until the adequate level of INR has been achieved, when the use of fraxarin is terminated 8 .
During the treatment at the Clinic of Dentistry, our patient had the INR controlled on a daily basis, which is in accordance with the recommendations of the British Association of Haematologists 14 .
The presented patient had previously increased the dose of OAT four times, on his own initiative.Consequently, the blood coagulation ability (INR>8) decreased drastically, which, along with minimal buccal mucosa tissue trauma (decubitus) provoked by sharp edges of the lower right first molar, caused considerable bleeding and the formation of a large hematoma.
At first, the patient received fresh frozen plasma to replenish the blood lost due to the haematocrit which was suggestive of that.Fresh frozen plasma contains all stable and unstable factors of the system of coagulation, fibrinolysis and complements, along with effective proteins and immunoglobulins.It is mainly used in patients with many coagulation factors deficiencies, sometimes with deficiencies of certain factors when concentrated preparations are missing 6,17 .It is also used in patients with an impaired liver function or vitamin K deficiencies, that is, in cases of overdosing with its antagonists, which was the case with our patient.
Antibiotics were administered to prevent the occurrence of an infection given that the blood which poured out represents a suitable medium for the appearance and development of an infection.
The suspension of OAT and switching to Fraxarin in target doses affected the improvement of the general condition and the reduction of the hematoma, which eventually resulted in complete recovery.The treatment of the sharp edges of all teeth, especially teeth that caused decubitus, excluded potential causes of further buccal mucosa damage.

Conclusion
Regular laboratory control of OAT via the INR test is mandatory in order to spot a decrease or increase in drug levels in time and maintain its target value.In addition, patient education plays a crucial role.Since doctors are very often dealing with old and uninformed patients, they have to explain thoroughly the dangers of OAT in terms of dose reduction and risks of worsening the underlying disease, as well as the dangers of overdosing and risks of sudden bleeding.Complications, which can sometimes be lifethreatening, may arise in both cases.

Slika 1 .
Pacijent sa perioralnim hematomom (prednji izgled lica) Figure1.Patient with perioral haematoma (anterior viewof the face)Case studyPatient S.S., male, aged 79, was admitted to the Oral Surgery Department, Dentistry Clinic of the Faculty of Medicine in Niš on October 5, 2012 due to a severe general condition with massive hematoma in the facial area (Figure1, 2).

Slika 7
Ortopantomografski prikaz bezubih predela i oštrih ivica zuba Figure7Panoramic view of present edentulousness and scharp enamel edges of the present teeth