Review Article Sri Lanka Dental Journal 2016; 46(01) 05-13

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1 Review Article Sri Lanka Dental Journal 2016; 46(01) The Importance of Knowing the Patient s Clotting Profile before Dental Treatment N.A. Alles, N.S. Soysa Introduction Patients having bleeding disorders have an increased risk of significant bleeding from invasive dental and oral surgery procedures. Excessive bleeding poses a heavy burden especially on general dental practitioners as many private dental clinics are not equipped to deal with profuse bleeding encountered in patients with bleeding disorders. In addition to the promotion of prevention of dental diseases, the emergence of newer materials, local haemostatic agents and minimally invasive procedures have disencumbered the difficulties encountered in managing patients having bleeding disorders like hemophilia during invasive dental treatment procedures. Not only congenital disorders congenital disorders, liver diseases such as cirrhosis, platelet deficiency, scurvy, but also chronic anticoagulant therapy cause prolonged bleeding in patients following invasive dental treatment. Therefore, understanding the bleeding and coagulation profiles of a patient is important for the safe and successful management of dental patients in both private and government hospitals. Hemostasis requires intact endothelium, an adequate number of platelets, clotting factors and the von Willibrand Factor (vwf) which facilitates platelet adherence to the damaged endothelial wall. The process of hemostasis can be described under primary hemostasis, secondary hemostasis, formation and stabilization of fibrin clot and fibrinolysis. In the event of an injury, primary hemostasis takes place which results in the contraction of the smooth muscles of the blood vessels to minimize the opening of the injury or the penetration of vessel followed by the adherence of platelets to the injured site forming a platelet plug with the aid of the vwf (Figure 1). Once adhered to the injured site, platelets change their morphology and degranulate attracting more and more platelets to the site to close the opening. The inactive soluble clotting factors in the circulation become activated as a result of the activation of the coagulation/ clotting cascade in the secondary hemostasis, and then form the fibrin which entraps platelets and red blood cells (RBCs) resulting in the organized clot 1. Hence, a better understating of the role of the platelets and coagulation cascade which is measured by coagulation tests such as the thrombin time (TT), prothrombin time (PT), and activated partial thromboplastin time (aptt) are important 2 when handling dental patients who require invasive dental treatments such as extractions, periodontal surgery and other minor surgeries etc. Platelets Platelets are derived from megakaryocytes and have a life span of 7-12 days. Platelets are usually stored and recycled in the spleen. Activation of platelets result in degranulation of certain Dr. N.A. Alles Dr. N.S. Soysa (Correspondence) (BVSc, PhD), Department of Biochemistry, Faculty of Medicine, University of Peradeniya. (BDS, PhD) Department of Oral Medicine and Periodontology, Faculty of Dental Sciences, University of Peradeniya. niroshanis@pdn.ac.lk 5

2 N.A. Alles, N.S. Soysa Figure 1. molecules including adenosine diphosphate (ADP), serotonin, calcium, fibrinogen, the platelet factor 4, clotting factor V, platelet-derived growth factor (PDGF), thrombospondin, and the vwf (Figure 2). With the aid of vwf, platelets adhere to the injured site of the endothelium and release the aforementioned chemical mediators attracting more and more platelets in addition to activating clotting cascade and vasoconstriction (Figure 1). Attachment of platelet-to-platelet occurs through fibrinogen which is bound to the glycoprotein IIb-IIIa receptors on the platelet surface 3 (Figure 2). Once activated, platelets synthesize the vasoconstrictor thromboxane A2 (TXA 2 ) from arachidonic acid via the cyclooxygenase (COX) pathway. The appearance of negatively charged phospholipids on the surface of platelets activates the intrinsic pathway of coagulation cascade. The clotting factor V (labile factor) is released by the platelets, further facilitating the clotting cascade. Finally, platelet actinomycin contracts, pulling the clot into a tight plug 4. The normal platelet count is usually lies within the range of x 10 9 /L (150, 000 to 450, 000 cells/mm 3 ). The acceptable lower value for dental surgery is 50 x 10 9 /L 5. Though patients having counts of less than 100 x 10 9 /L might bleed, the local measures such as suturing and the placing of a haemostatic is adequate to control the bleeding successfully. Lower platelet counts less than 50 x 10 9 /L (50,000 cells/mm 3 ) require replacement therapy 5. Usually it is recommended to administer platelet (transfusion) 30 minutes prior to surgery. In the event of immune-mediated idiopathic thrombocytopenia, pre-operative oral systemic steroids are given for 7 to 10 days to increase the platelet counts to a more acceptable level 6. A novel method of analyzing platelet function using PFA-100, a platelet function analyzer (PFA) has been developed to screen the function of platelets. In the event of unavailability of this PFA-100, measuring bleeding time is also effective in delineating the platelet function. Bleeding time of 3 to 8 minutes gives an idea about intact platelet function, vwf, and an intact coagulation cascade. Bleeding Time Bleeding time measures the time taken to form the hemostatic plug after a standard skin incision (a superficial incision which is less than 1 mm deep and 1 cm long) of the forearm (or earlobe) using a special instrument. The Duke 6

3 The Importance of Knowing the Patient s Clotting Profile before Dental Treatment Figure 2. method and Ivy method are some of the methods available to perform bleeding time. The normal range of the Ivy Bleeding Time Test is usually between 2 and 10 minutes. In addition, there are several commercially available bleeding time devices such as the Simplate and Surgicutt. Von Willibrand Factor (vwf) The von Willebrand factor (vwf) is synthesized by endothelial cells as well as platelets. The vwf facilitates the adherence of platelets to the damaged vessel walls. Lack of vwf results in bleeding due to the inability of platelets to adhere to the vessel wall and their subsequent activation and degranulation. Moreover, vwf acts as a carrier for clotting factor VIII thereby, preventing its degradation and prolonging the half-life of factor VIII. In fine, deficiency of vwf reduces platelet adherence, activation as well as the levels of factor VIII. Clotting Factors Secondary hemostasis occurs as a result of intricate and interrelated systems of coagulation cascade. The inactive clotting factors (Table 1) get activated via two pathways; namely intrinsic and extrinsic pathways (Figure 3). The activation of intrinsic pathway involves initial activation of inactive factor XII by the negatively charged collagen found in the damaged endothelium. This initiates a cascade of events leading to the common pathway, where intrinsic and extrinsic pathways converge to form insoluble fibrin from fibrinogen (Figure 3). In the laboratory, the intactness of intrinsic pathway is performed by measuring the activated partial thromboplastin time (aptt). The activation of extrinsic pathway occurs subsequent to the release of tissue factor following endothelial damage. This activates the factor VII (proconvertin or stable factor) and ultimately the common pathway. The activation of common pathway involves the activation of factor X (Stuart factor) which in turn converts prothrombin (factor II) to thrombin, and finally fibrinogen (factor I) to fibrin. In addition, thrombin enhances the conversion of Factor V to Va, Factor VIII to VIIIa and thus amplifying the coagulation cascade. Prothrombin time (PT) is used to assess the integrity of extrinsic and common pathways (Figure 3). Except for factor VII, almost all the clotting factors are synthesized in the liver and in addition, vitamin K is required for the synthesis of factor II (prothrombin), factor VII, factor IX (Christmas factor), and factor X. The anticoagulant warfarin interferes with the synthesis of vitamin K dependent factors by preventing the reduction of vitamin K. 7

4 N.A. Alles, N.S. Soysa Table 1. Factor Name Comments I Fibrinogen II Prothrombin Vitamin K dependent factor III Thromboplastin IV Calcium V Labile factor VII Proconvertin or stable factor Vitamin K dependent factor VIII Antihemophilic factor IX Christmas factor Vitamin K dependent factor X Stuart factor Vitamin K dependent factor XI Plasma thromboplastin antecedent XII Hageman factor XIII Fibrin-stabilizing factor Figure 3. Prothrombin time (PT) Prothrombin time (PT) measures the function of the extrinsic pathway (Figure 4). Factor III or tissue factor (also known as thromboplastin or CD142), which is a transmembrane protein that activates factor VII and initiates the extrinsic coagulation pathway. The tissue factor is expressed by cells of non-vascular origin as well as by subendothelial tissues and leukocytes (monocytes). Since three of the clotting factors 8 involved (II, VII, X) are vitamin K dependent, PT is also used to measure liver function. In the laboratory, PT is measured by mixing calcium and thromboplastin with citrated plasma (blood is collected into a tube with sodium citrate which chelates calcium thus preventing blood clotting during transport) and then allowing it to coagulate. The time taken to form the clot is considered as PT (Figure 4). Though the normal value of PT varies from lab to lab, usually

5 The Importance of Knowing the Patient s Clotting Profile before Dental Treatment the normal PT ranges from 9 to 15 seconds. However, the PT should be always compared to the reference range given by the particular laboratory. Thromboplastin is usually derived from animal tissues that provide the tissue factor as well as phospholipids (PL) necessary for the activation of factor VII and then factor X. Due to the differences in commerciallyproduced thromboplastins throughout the world, the World Health Organization (WHO) introduced the International Normalized Ratio (INR) which is devised to normalize the clotting time by correcting the differences in reagent responsiveness, and to facilitate the standardization of laboratory testing of PT 7. Thromboplastin used by each laboratory is tested against an international standard and then the relationship is given as international sensitivity index (ISI). The INR uses the ISI to equate all thromboplastins to the reference thromboplastin and commercial suppliers of thromboplastin usually gives the ISI with each reagent lot. If the ISI is known, the INR is easily calculated through the following equation: INR = (patient PT/mean normal PT) ISI Normally, thromboplastins with lower ISI values (close to 1) are more accurate and show the effects of anticoagulants such as warfarin well and also have a longer PT. For example, when a blood sample is analyzed using two thromboplastin reagents with two different ISIs, the PT will be higher with the more sensitive (lower ISI) thromboplastin than with less sensitive (higher ISI) thromboplastin; however, the INR values will be equivalent in both situations. The normal value of the INR for a healthy person ranges between Depending on the type of medical condition, the desirable INR given for patients on anticoagulant therapy varies and needs to be within the theraputic range; however, usually it is less than 4.0. It is advisable to measure the INR of patients on warfarin therapy before invasive dental treatments 8. Figure 4. 9

6 N.A. Alles, N.S. Soysa Activated Partial Thromboplastin Time (aptt) This test evaluates the intrinsic and common pathways of blood coagulation. Activated partial thromboplastin time (aptt) gives an idea about the deficiencies of the clotting factors in the intrinsic pathway such as XII, XI, IX, VIII, and the common pathway factors X and V and prothrombin and fibrinogen (Figure 4). A normal aptt is about 25 to 40 seconds. The various aptt reagents contain phospholipids and a specific contact activator. The aptt is commonly employed in monitoring heparin therapy and to diagnose hemophilias (Table 2). Thrombin Time (TT) Thrombin Time (TT) denotes the formation of an insoluble clot by conversion of fibrinogen to insoluble fibrin. TT evaluates lack of fibrinogen or the presence of an inhibitor of thrombin (Factor IIa). Anticoagulant drug therapy (e.g. heparin or direct thrombin inhibitor) causes prolongation of TT. This laboratory test is performed by adding thrombin to the patient s blood sample which circumvents the intrinsic, extrinsic and common pathways to determine the stability of the clot. Thrombin Time (TT) ranges between 9 to 13 seconds. Table 2. Test Normal range Conditions with normal vales Conditions with elevated vales Conditions with reduced vales Bleeding time aptt 3-8 min s Hemophilia A and B Von Willebrand disease Hemophilia A and B, disseminated intravascular coagulation (DIC), liver disease, vitamin K deficiency, warfarin therapy PT INR TT Factor V Factor VII 9-15 s s % Hemophilia A and B Vitamin K deficiency DIC, liver disease, vitamin K deficiency,warfarin therapy Liver disease, DIC Liver disease, vitamin K deficiency, DIC Factor VIII % Liver disease, vitamin K deficiency Liver disease Hemophilia A, von Willebrand disease, DIC 10

7 The Importance of Knowing the Patient s Clotting Profile before Dental Treatment Management of Bleeding During Dental Procedures Systemic Therapies Unlike patients having severe and moderate haemophilia which give rise to spontaneous bleeding, mild haemophilia may not be diagnosed until a procedure such as a dental extraction causes prolonged bleeding. If it is known that the patient is having haemophilia, it is imperative that dental treatments are scheduled to be performed \at times of factor administration and thereby reduce the risks of therapies subsequent to heavy bleeding. Clinical manifestations of von Willebrand disease might include signs and symptoms such as mucocutaneous haemorrhage and gingival bleeding which are characteristic features of platelet dysfunction. However, if not diagnosed previously, bleeding after dental extractions may be a presenting feature of the von Willebrand disease. Factor XI deficiency might manifest by mild unpredictable bleeding which may aggravate following surgery such as tonsillectomy and dental procedures in areas with high fibrinolytic activity. Since the current practice is to use factor concentrates for all known factor deficiencies, if available, management of the condition requires administration of fresh frozen plasma or the administration of factor XI concentrates in addition to antifibrinolytics. In fine, the aforementioned bleeding disorders require coagulation factor replacement, desmopressin (DDAVP) to release endogenous factor stores, antifibrinolytics and local measures to achieve hemostasis following invasive dental procedures. However, oral examinations, application of fissure sealants, small occlusal restorations without local anesthesia and supragingival scaling do not require such therapy 9. Though local anesthetic infiltration can be achieved by slow injection technique with a fine gauge single-use needle without factor replacement therapy, augmentation of factor levels with or without tranexamic acid is required when inferior alveolar and posterior superior alveolar dental nerve blocks are given in patients having hemophilia Therefore it is obvious that depending on the bleeding disorder and the type of dental procedure, the type of systemic therapies varies and the decision for coagulation factor replacement should be made with the consultation of a hematologist. It is advisable to perform invasive dental procedures which require factor replacement in a hospital setup which is more equipped with emergency management than a general practice. Use of Antifibrinolytic Agents Aminocaproic acid and tranexamic acid are synthetic products that prevent fibrinolysis by blocking the binding of plasminogen to fibrin and its subsequent activation to plasmin. Normally, plasminogen activators are abundant in oral mucosa. In addition, saliva shows ample fibrinolytic activity. Therefore, aminocaproic acid and tranexamic acid can be administered to prevent clot lysis after oral surgery or dental extractions. For example, it has been shown that tranexamic acid significantly reduces the risk of delayed bleeding and the amount of clotting factor replacement therapy required after dental surgery in haemophiliacs 10. In those instances, administration of tranexamic acid commences before surgery at a dose of 25 mg/kg t.i.d and continues for 3-5 days as post extraction therapy. These agents are also available as mouthwashes; therefore, can be used as a local therapy in patients on oral anticoagulants, without reducing or withholding the anticoagulant therapy 11. Patients on Antithrombotic/Anticoagulant Therapy Earlier, the common practice was to discontinue medication such as warfarin for at least 2 days before dental procedures in patients on longterm anticoagulation or antiplatelet therapy. However, due to the fact that the risk of thromboembolism outweighs the beneficial effects of temporary cessation of therapy, it is not advisable to stop taking warfarin during dental treatments, provided that the INR is within the acceptable range. Moreover, it has

8 N.A. Alles, N.S. Soysa been shown that local measures are adequate to prevent or reduce the bleeding 8. A systematic review and a meta analysis revealed that continuing the regular warfarin therapy does not cause excessive bleeding compared to that of discontinuing or modifying the dose for patients who undergo minor dental procedures such as dental extractions Managing Postoperative Bleeding of Patients on warfarin after Extraction: 1. packing the sockets with oxidized cellulose, reabsorbable collagen sponges, fibrin adhesives, tissue adhesives and suturing 2. application of pressure packs - it is important to keep the pressure pack at the extraction socket at least ½ hr without checking it for bleeding at the extraction socket 3. additional injection of a local anesthetic with epinephrine to retard the bleeding and enhances the vessel constriction, platelet plug formation and stable clot formation 4. advice the patients to limit physical exertion, rinsing the mouth, sucking or chewing food on the affected side until the clot is formed 5. advice patients to refrain from taking NSAIDS as pain killers following dental treatment since, patients may experience pain or discomfort once the local anesthesia wanes off. Paracetamol is the safest analgesic for patients at risk of bleeding (e.g. patientss on warfarin) after invasive dental treatments. There are several lines of evidence to show that when combined with local hemostatic measures and suturing, tranexamic acid mouthwashes do not provide additional effects in reducing postoperative bleeding 14. Summary Excessive bleeding following minor dental procedures such as extractions preclude the dentists to handle patients having bleeding disorders and antithrombotic therapies including warfarin therapy. However, evidence indicates that the cessation of anticoagulant therapies is not indicated given the fact that the patient s INR is obtained prior to the invasive procedure and the local hemostatic measures are available at hand. This signifies the importance of understanding hemostasis and the various laboratory tests used to evaluate bleeding in dental patients. References 1. Platt, A. Understanding and treating disorders of the clotting system. JAAPA Off. J. Am. Acad. Physician Assist. 20, (2007). 2. Mani, H. Interpretation of coagulation test results under direct oral anticoagulants. Int. J. Lab. Hematol. 36, (2014). 3. Vorchheimer, D. A. & Becker, R. Platelets in atherothrombosis. Mayo Clin. Proc. 81, (2006). 4. Kickler., T. Platelet biology - an overview. Transfus. Altern. Transfus. Med. 2, (2006). 5. Gupta A1, Epstein JB, Cabay RJ. Bleeding disorders of importance in dental care and related patient management. J Can Dent Assoc, 73(1):77-83( 2007). 6. Meechan, J. G. & Greenwood, M. General medicine and surgery for dental practitioners Part 9: haematology and patients with bleeding problems. Br. Dent. J. 195, (2003). 7. Stern, R., Karlis, V., Kinney, L. & Glickman, R. Using the international normalized ratio to standardize prothrombin time. J. Am. Dent. Assoc , (1997). 8. Soysa, N. Managing patients receiving warfarin therapy in general dental practice. Gen. Dent. Pract. 30, (2013). 12

9 The Importance of Knowing the Patient s Clotting Profile before Dental Treatment 9. Anderson, J. a. M. et al. Guidance on the dental management of patients with haemophilia and congenital bleeding disorders. Br. Dent. J. 215, (2013). 10. Sindet-Pedersen, S. & Stenbjerg, S. Effect of local antifibrinolytic treatment with tranexamic acid in hemophiliacs undergoing oral surgery. J. Oral Maxillofac. Surg. Off. J. Am. Assoc. Oral Maxillofac. Surg. 44, (1986). 11. Israels, S., Schwetz, N., Boyar, R. & McNicol, A. Bleeding disorders: characterization, dental considerations and management. J. Can. Dent. Assoc. 72, 827 (2006). 12. Nematullah A, Alabousi A, Blanas N, Douketis JD, Sutherland SE. Dental surgery for patients on anticoagulant therapy with warfarin: a systematic review andmeta-analysis.tex Dent J Dec;126(12): Nematullah A, Alabousi A, Blanas N, Douketis JD, Sutherland SE. Dental surgery for patients on anticoagulant therapy with warfarin: a systematic review andmeta-analysis.j Can Dent Assoc Feb;75(1): van Galen KP, Engelen ET, Mauser- Bunschoten EP, van Es RJ, Schutgens RE. Antifibrinolytic therapy for preventing oral bleeding in patients with haemophilia or Von Willebrand disease undergoing minor oral surgery or dental extractions. Cochrane Database Syst Rev Dec 24;12:CD