Hemostasis of blood

HEMOSTASIS OF BLOOD by DR SANDIP BHATTACHARYYA.

1. HEMOSTASIS OF BLOOD

2. Hemostasis is a precisely orchestrated process involving platelets, clotting factors, and endothelium that occurs at the site of vascular injury and culminates in the formation of a blood clot, which serves to prevent or limit the extent of bleeding. Four major physiologic events participate in the hemostatic process: vascular constriction , platelet plug formation , fibrin formation , and fibrinolysis . Although each tends to be activated in order, the four processes are interrelated so that there is a continuum and multiple reinforcements.

3. V ascular constriction Arteriolar vasoconstriction occurs immediately and markedly reduces blood flow to the injured area. The contraction results from-------- local myogenic spasm . local autacoid factors from the traumatized tissues and blood platelets. nervous reflexes . (The nervous reflexes are initiated by pain nerve impulses or other sensory impulses that originate from the traumatized vessel or nearby tissues.). The more severely a vessel is traumatized, the greater the degree of vascular spasm. The spasm can last for many minutes or even hours, during which time the processes of platelet plugging and blood coagulation can take place.

4. Thromboxane A2 (TXA2), from platelet membranes and Endothelin [synthesized by injured endothelium and serotonin (5-hydroxytryptamine [5-HT]) released during platelet aggregation ] are potent vasoconstrictors. Bradykinin and fibrinopeptides , which are involved in the coagulation schema, are also capable of contracting vascular smooth muscle.

5. Primary hemostasis: the formation of the platelet plug . Disruption of the endothelium exposes subendothelial von Willebrand factor ( vWF ) and collagen, which promote platelet adherence and activation. Activation of platelets results in a dramatic shape change (from small rounded discs to flat plates with spiky protrusions that markedly increased surface area), as well as the release of secretory granules. Within minutes the secreted products recruit additional platelets, which undergo aggregation to form a primary hemostatic plug.

6. Secondary hemostasis: deposition of fibrin Tissue factor is also exposed at the site of injury. Tissue factor is a membrane-bound procoagulant glycoprotein that is normally expressed by subendothelial cells in the vessel wall, such as smooth muscle cells and fibroblasts. Tissue factor binds and activates factor VII , setting in motion a cascade of reactions that culiminates in thrombin generation. Thrombin cleaves circulating fibrinogen into insoluble fibrin, creating a fibrin meshwork, and also is a potent activator of platelets, leading to additional platelet aggregation at the site of injury. This sequence, referred to as secondary hemostasis,consolidates the initial platelet plug.

7. Clot stabilization and resorption . Polymerized fibrin and platelet aggregates undergo contraction to form a solid, permanent plug that prevents further hemorrhage. At this stage, counterregulatory mechanisms (e.g., tissue plasminogen activator, t-PA) are set into motion that limit clotting to the site of injury and eventually lead to clot resorption and tissue repair.

8. Platelets Platelets are disc-shaped anucleate cell fragments that are shed from megakaryocytes in the bone marrow into the bloodstream. Platelets play a critical role in hemostasis by forming the primary plug that initially seals vascular defects and by providing a surface that binds and concentrates activated coagulation factors. Their function depends on several glycoprotein receptors , a contractile cytoskeleton , and two types of cytoplasmic granules . α-Granules have the adhesion molecule P- selectin on their membranes and contain proteins involved in coagulation, such as fibrinogen, coagulation factor V, and vWF , as well as protein factors that may be involved in wound healing,such as fibronectin , platelet factor 4 (a heparin-binding chemokine), platelet-derived growth factor (PDGF), and transforming growth factor-β.

9. Dense (or δ) granules contain adenosine diphosphate (ADP) and adenosine triphosphate, ionized calcium, serotonin, and epinephrine. After a traumatic vascular injury, platelets encounter constituents of the subendothelial connective tissue, such as vWF and collagen. On contact with these proteins, platelets undergo a sequence of reactions that culminate in the formation of a platelet plug.

10. Platelet adhesion is mediated largely via interactions with vWF , which acts as a bridge between the platelet surface receptor glycoprotein Ib ( GpIb ) and exposed collagen . Notably, genetic deficiencies of vWF (von Willebrand disease ) or GpIb (Bernard- Soulier syndrome) result in bleeding disorders, attesting to the importance of these factors.

11. Platelets rapidly change shape following adhesion, being converted from smooth discs to spiky “sea urchins” with greatly increased surface area. This change is accompanied by alterations in glycoprotein IIb / IIIa that increase its affinity for fibrinogen, and by the translocation of negatively charged phospholipids (particularly phosphatidylserine ) to the platelet surface. These phospholipids bind calcium and serve as nucleation sites for the assembly of coagulation factor complexes. Secretion (release reaction) of granule contents occurs along with changes in shape; these two events are often referred to together as platelet activation . Platelet activation is triggered by a number of factors, including the coagulation factor thrombin and ADP .

12. Thrombin activates platelets through a special type of G-protein coupled receptor referred to as a protease-activated receptor (PAR), which is switched on by a proteolytic cleavage carried out by thrombin. ADP is a component of dense body granules; thus, platelet activation and ADP release begets additional rounds of platelet activation, a phenomenon referred to as recruitment . Activated platelets also produce the prostaglandin thromboxane A2 (TxA2), a potent inducer of platelet aggregation. Aspirin inhibits platelet aggregation and produces a mild bleeding defect by inhibiting cyclooxygenase, a platelet enzyme that is required for TxA2 synthesis.

13. Platelet aggregation follows their activation. The conformational change in glycoprotein IIb / IIIa that occurs with platelet activation allows binding of fibrinogen, a large bivalent plasma polypeptide that forms bridges between adjacent platelets, leading to their aggregation. The initial wave of aggregation is reversibl e, but concurrent activation of thrombin stabilizes the platelet plug by causing further platelet activation and aggregation, and by promoting irreversible platelet contraction . Platelet contraction is dependent on the cytoskeleton and consolidates the aggregated platelets. In parallel, thrombin also converts fibrinogen into insoluble fibrin, cementing the platelets in place and creating the definitive secondary hemostatic plug.

14. BLOOD COAGULATION IN THE RUPTURED VESSEL During the 19th century, German pathologist Rudolf Virchow in 1860 (Nichols & Bowie, 2001) described thrombi (blood clots) and their tendency to embolize . Platelets were discovered, and their function was established, along with discovery of the various components of the coagulation process. These advances led to the classic theory of coagulation described by Paul Morawitz in 1905 (Morawitz,1958). He convincingly assembled 4 “coagulation factors” in his scheme of coagulation.

15. The modern understanding of the biochemical processes of coagulation began in the 1940s, when Paul Owren (1947) recognized that a bleeding diathesis in a young woman could not be explained by the 4-factor concept, positing that she lacked a fifth coagulation factor in her plasma. Throughout the 1940s and 1950s, several more coagulation factors were discovered. Coagulation factors were designated by roman numerals . The numeric system that was adopted assigned the number to the factor according to the sequence of discovery and not to the point of interaction in the cascade.

16. By 1957, the following factors were described:-- von Willebrand factor (VWF) (von Willebrand , 1931), factor (F) V ( Owren , 1947) FVII (Alexander, Goldstein, Landwehr , & Cook, 1951), FVIII ( Patek & Stetson, 1936), FIX ( Aggeler et al., 1952; Briggs et al., 1952; Shulman & Smith, 1952) FXI (Rosenthal, Dreskinoff , & Rosenthal, 1953).

17. In the 1960s, 2 independent groups of biochemists introduced a model of coagulation as a series of steps in which activation of each clotting factor led to the activation of another, culminating in a burst of thrombin generation. The article proposing the cascade model by Macfarlane (1964) appeared in the journal Nature and was shortly followed by the waterfall model reported by Davie and Ratnoff (1964) in the journal Science. The “cascade” and “waterfall” models suggested that the clotting sequences were divided into 2 pathways. Coagulation could be initiated via an “ intrinsic pathway ,” so named because all the components were present in blood. an “extrinsic pathway,” in which the subendothelial cell membrane protein, tissue factor (TF), was required in addition to circulating components. The initiation of either pathway resulted in activation of FX and the eventual generation of a fibrin clot through a common pathway ( Luchtman -Jones & Broze , 1995).

18. MECHANISM OF BLOOD COAGULATION More than 50 important substances that cause or affect blood coagulation have been found in the blood and in the tissues—some that promote coagulation, called procoagulants , and others that inhibit coagulation, called anticoagulants Whether blood will coagulate depends on the balance between these two groups of substances. In the blood stream, the anticoagulants normally predominate, so the blood does not coagulate while it is circulating in the blood vessels. However, when a vessel is ruptured, procoagulants from the area of tissue damage become “activated” and override the anticoagulants, and then a clot does develop.

19. Clotting takes place in three essential steps: In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reactions occurs in the blood involving more than a dozen blood coagulation factors. The net result is formation of a complex of activated substances collectively called prothrombin activator. The prothrombin activator catalyzes conversion of prothrombin into thrombin . The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells, and plasma to form the clot.

20. CONVERSION OF PROTHROMBIN TO THROMBIN

21. Clot Retraction and Expression of Serum Within a few minutes after a clot is formed, it begins to contract and usually expresses most of the fluid from the clot within 20 to 60 minutes. Platelets are necessary for clot retraction to occur. Therefore, failure of clot retraction is an indication that the number of platelets in the circulating blood might be low. Electron micrographs of platelets in blood clots show that they become attached to the fibrin fibers in such a way that they actually bond different fibers together. platelets entrapped in the clot continue to release procoagulant substances, one of the most important of which is fibrin-stabilizing factor, which causes more and more cross-linking bonds between adjacent fibrin fibers.

22. In addition, the platelets contribute directly to clot contraction by activating platelet thrombosthenin , actin, and myosin molecules, which are all contractile proteins in the platelets and cause strong contraction of the platelet spicules attached to the fibrin. This action also helps compress the fibrin meshwork into a smaller mass. The contraction is activated and accelerated by thrombin, as well as by calcium ions released from calcium stores in the mitochondria, endoplasmic reticulum, and Golgi apparatus of the platelets. As the clot retracts, the edges of the broken blood vessel are pulled together, thus contributing still further to hemostasis

23. FIBROUS ORGANIZATION OR DISSOLUTION OF THE BLOOD CLOT Once a blood clot has formed, it can follow one of two courses: It can become invaded by fibroblasts, which subsequently form connective tissue all through the clot. it can dissolve. The usual course for a clot that forms in a small hole of a vessel wall is invasion by fibroblasts, beginning within a few hours after the clot is formed (which is promoted at least partially by growth factor secreted by platelets). This process continues to complete organization of the clot into fibrous tissue within about 1to 2 weeks. Conversely, when excess blood has leaked into the tissues and tissue clots have occurred where they are not needed, special substances within the clot itself usually become activated. These substances function as enzymes to dissolve the clot.

24. INITIATION OF COAGULATION: FORMATION OF PROTHROMBIN ACTIVATOR Prothrombin activator is generally considered to be formed in two ways, although, in reality, the two ways interact constantly with each other: the extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues. the intrinsic pathway that begins in the blood. In both the extrinsic and the intrinsic pathways, a series of different plasma proteins called blood-clotting factors plays a major role. Most of these proteins are inactive forms of proteolytic enzymes. When converted to the active forms, their enzymatic actions cause the successive, cascading reactions of the clotting process.

25. Intrinsic pathway

26. Extrinsic Pathway

27. Interaction between the Extrinsic and Intrinsic Pathways A fter blood vessels rupture, clotting occurs by both pathways simultaneously. Tissue factor initiates the extrinsic pathway, whereas contact of Factor XII and platelets with collagen in the vascular wall initiates the intrinsic pathway. the extrinsic pathway once initiated, its speed of completion to the final clot is limited only by the amount of tissue factor released from the traumatized tissues and by the quantities of Factors X, VII, and V in the blood. With severe tissue trauma, clotting can occur in as little as 15 seconds. The intrinsic pathway is much slower to proceed, usually requiring 1 to 6 minutes to cause clotting.

28. The central role of thrombin in hemostasis Among the coagulation factors, thrombin is the most important, in that its various enzymatic activities control diverse aspects of hemostasis and link clotting to inflammation and repair. Among thrombin’s most important activities are the following: Conversion of fibrinogen into crosslinked fibrin . Thrombin directly converts soluble fibrinogen into fibrin monomers that polymerize into an insoluble clot, and also amplifies the coagulation process, not only by activating factor XI, but also be activating two critical co-factors, factors V and VIII. It also stabilizes the secondary hemostatic plug by activating factor XIII, which covalently cross-links fibrin. Platelet activation . Thrombin is a potent inducer of platelet activation and aggregation through its ability to activate PARs, thereby linking platelet function to coagulation.

29. Pro-inflammatory effects PARs are also expressed on inflammatory cells, endothelium, and other cell types , and activation of these receptors by thrombin is believed to mediate proinflammatory effects that contribute to tissue repair and angiogenesis. Anticoagulant effects upon encountering normal endothelium thrombin changes from a procoagulant to an anticoagulant. This reversal in function prevents clotting from extending beyond the site of the vascular injury.

30. Factors That Limit Coagulation . Endothelial Surface Factors : Platelet inhibitory effects — An obvious effect of intact endothelium is to serve as a barrier that shields platelets from subendothelial vWF and collagen. normal endothelium also releases a number of factors that inhibit platelet activation and aggregation like prostacyclin (PGI2), nitric oxide (NO), and adenosine diphosphatase ; the latter degradesADP , act as potent activator of platelet aggregation. endothelial cells bind and alter the activity of thrombin, which is one of the most potent activators of platelets.

31. Anticoagulant effects . Normal endothelium shields coagulation factors from tissue factor in vessel walls and expresses multiple factors that actively oppose coagulation, most notably thrombomodulin , endothelial protein C receptor, heparin-like molecules, and tissue factor pathway inhibitor. Thrombomodulin and endothelial protein C receptor bind thrombin and protein C, respectively, in a complex on the endothelial cell surface. When bound in this complex, thrombin loses its ability to activate coagulation factors and platelets, and instead cleaves and activates protein C, a vitamin K–dependent protease that requires a cofactor, protein S. Activated protein C/protein S complex is a potent inhibitor of coagulation factors Va and VIIIa .

32. Heparin-like molecules on the surface of endothelium bind and activate antithrombin III, which then inhibits thrombin and factors IXa , Xa , XIa , and XIIa . Tissue factor pathway inhibitor (TFPI), like protein C, requires protein S as a cofactor and, as the name implies, binds and inhibits tissue factor/factor VIIa complexes. Fibrinolytic effects . Normal endothelial cells synthesize t-PA , act as a key component of the fibrinolytic pathway.

33. Activation of Plasminogen to Form Plasmin The plasma proteins contain a euglobulin called plasminogen (or profibrinolysin ) that, when activated, becomes a substance called plasmin (or fibrinolysin ). The injured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator (t-PA); a few days later, after the clot has stopped the bleeding, t-PA eventually converts plasminogen to plasmin , which in turn removes the remaining unnecessary blood clot. Plasmin digests fibrin fibers and some other protein coagulants such as fibrinogen, Factor V, Factor VIII, prothrombin , and Factor XII. important function of the plasmin system is to remove minute clots from millions of tiny peripheral vessels that eventually would become occluded were there no way to clear them.

34. Laboratory Tests BLEEDING TIME ---- The Ivy bleeding time (BT) has been used to screen for disorders of platelet function and thrombocytopenia. Normal value --1 to 6 minutes. The platelet function analyzer (PFA- 100), an instrument that measures platelet-dependent coagulation under flow conditions, is more sensitive and specific for platelet disorders and von Willebrand disease ( vWD ) than the bleeding time. however, it is not sensitive enough to rule out underlying mild bleeding disorders. Also, it has not been evaluated prospectively to determine its utility in predicting bleeding risk, although such studies are underway. Therefore, the BT and PFA-100 are not recommended as screening tests to be used by the dentist

35. CLOTTING TIM E---- The one most widely used is to collect blood in a chemically clean glass test tube and then to tip the tube back and forth about every 30 seconds until the blood has clotted. By this method, the normal clotting time is 6 to 10 minutes. Unfortunately, the clotting time varies widely, depending on the method used for measuring it, so it is no longer used in many clinics. Screening Tests :---- Three tests are recommended for use in initial screening for possible bleeding disorders. activated partialthromboplastin time ( aPTT ), prothrombin time (PT), and platelet count . An additional test can be added to the initial screen: the thrombin time (TT).

36. Partial Thromboplastin Time — Partial thromboplastin time (PTT) is used to check the intrinsic system (factors VIII, IX, XI, and XII) and the common pathways (factors V and X, prothrombin , and fibrinogen). It also is the best single screening test for coagulation disorders. A phospholipid platelet substitute is added to the patient’s blood to initiate the coagulation process via the intrinsic pathway. When a contact activator, such as kaolin, is added, the test is referred to as activated PTT ( aPTT ). In general, aPTT ranges from 25 to 35 seconds, and results in excess of 35 seconds are considered abnormal or prolonged. The aPTT is prolonged in cases of mild to severe deficiency of factor VIII or IX.

37. Prothrombin Time — The prothrombin time (PT) is used to check the extrinsic pathway (factor VII) and the common pathway (factors V and X, prothrombin , and fibrinogen). For this test, tissue thromboplastin is added to the test sample to serve as the activating agent. In general, the normal range is 11 to 15 seconds. When the test is used to evaluate the level of anticoagulation with coumarin -like drugs the INR format is recommended. The normal range for INR in a healthy person is 0.9 to 1.3. The recommended INR goal for a patient on low-intensity warfarin therapy is 2.5, with a range of 2.0 to 3.

38. Platelet Count- -- Platelet count is used to screen for possible bleeding problems due to thrombocytopenia. Normal platelet count is 140,000 to 400,000/ μL of blood. Patients with a platelet count of between 50,000 and 100,000/ μL manifest excessive bleeding only with severe trauma. Patients with counts below 50,000/ μL demonstrate skin and mucosal purpura and bleed excessively with minor trauma. Patients with platelet counts below 20,000/ μL may experience spontaneous bleeding.

39. Thrombin Time — In this test, thrombin is added to the patient’s blood sample as the activating agent. It converts fibrinogen in the blood to insoluble fibrin, which makes up the essential portion of a blood clot. This test bypasses the intrinsic, extrinsic, and most of the common pathway. For example, patients with hemophilia A or factor V deficiency have a normal TT. Generally, the normal range for the TT test is 9 to 13 seconds, and results in excess of 16 to 18 seconds are considered abnormal or prolonged. Abnormal test results usually are caused by excessive plasmin or fibrin split products.

40. CONGENITAL FACTOR DEFICIENCIES Hemophilia A --- The hemostatic abnormality in hemophilia A is caused by a deficiency or a defect of factor VIII. Factor VIII was thought to be produced by endothelial cells and not by the liver, as most coagulation factors are. Hemophilia A is inherited as an X-linked recessive trait. The defective gene is located on the X chromosome (F8 gene). Hemophilia A can manifest in women. Normal homeostasis requires at least 30% factor VIII activity. Severe forms of the disease occur when the level is less than 1% of normal. Clinical Findings--- Patients with severe hemophilia (less than 1% of factor VIII) may experience severe, spontaneous bleeding.

41. Hemarthrosis , ecchymoses , and soft tissue hematomas are common. Spontaneous bleeding from the mouth, gingiva, lips, tongue, and nose may occur in these patients. This bleeding may be massive and life-threatening, or it may persist as a slow, continuous oozing for days, weeks, or months. Laboratory Tests---Screening tests that show prolonged aPTT , normal PT, and normal platelet count (except in some cases of von Willebrand disease) indicate a problem in the intrinsic pathway

42. Hemophilia B. In hemophilia B (Christmas disease), factor IX is deficient or defective. Hemophilia B is inherited as an X-linked recessive trait (F9 gene). Similar to hemophilia A, the disorder manifests primarily in males. Clinical manifestations of the two disorders are identical. Screening laboratory test results are similar for both diseases. Specific factor assays for factor IX establish the diagnosis. Purified factor IX products are recommended for the treatment of minor and major bleeding

43. von Willebrand Disease . The most common inherited bleeding disorder is von Willebrand disease, which is caused by an inherited defect involving platelet adhesion. The cause of platelet dysfunction in von Willebrand disease is a deficiency or a qualitative defect in vWF , which is made from a group of glycoproteins produced by megakaryocytes and endothelial cells. They are formed into a single monomer that polymerizes into huge complexes, which are needed to carry (bind) factor VIII and to allow platelets to adhere to surfaces. Unbound factor VIII is destroyed in the circulation. Most of the variants are transmitted as autosomal dominant traits (types 1 and 2). Type 1 is the most common form of von Willebrand disease. It accounts for about 70% to 80% of the cases.

44. Clinical Findings- --- Mild variants of von Willebrand disease are characterized by a history of cutaneous and mucosal bleeding because platelet adhesion is lacking. In the more severe forms of the disease, in which factor VIII levels are low, hemarthroses and dissecting intramuscular hematomas are part of the clinical picture. Serious bleeding can occur in these patients after trauma or surgical procedures. Laboratory Tests --- Screening laboratory tests may show prolonged aPTT , normal or slightly reduced platelet count, normal PT, and normal TT. Additional laboratory tests are needed to establish the diagnosis and type of von Willebrand disease. These consist of ristocetin cofactor activity, ristocetin -induced platelet aggregation, immunoassay of vWF , multimeric analysis of vWF , and specific assays for factor VIII.

45. Factor XI Deficiency- -- Factor XI deficiency, an autosomal recessive inherited condition sometimes referred to as hemophilia C, is more prevalent in the Ashkenazi Jewish population but found in all races. Spontaneous bleeding is rare, but bleeding may occur after surgery, trauma, or invasive procedures. Deficiency of Factors II ( Prothrombin ), V, and X- --- These deficiencies are inherited as autosomal recessive. Treatment of bleeding in individuals with the combined deficiency requires factor VIII concentrate and FFP. Some patients with factor V deficiency are also lacking the factor V normally present in platelets and may need platelet transfusions as well as FFP.

46. Factor VII Deficiency- -- Inherited factor VII deficiency is a rare autosomal recessive disorder. Bleeding is uncommon unless the level is less than 3%. The most common bleeding manifestations involve easy bruising and mucosal bleeding, particularly epistaxis or oral mucosal bleeding. Treatment is with FFP or recombinant factor VIIa . Factor XIII Deficiency ---- Congenital factor XIII (FXIII) deficiency, originally recognized by Duckert in 1960, is a rare autosomal recessive disease usually associated with a severe bleeding diathesis. Bleeding is typically delayed because clots form normally but are susceptible to fibrinolysis. Umbilical stump bleeding is characteristic, and there is a high risk of intracranial bleeding. Replacement can be accomplished with FFP, cryoprecipitate, or a factor XIII concentrate.

47. Platelet Functional Defects Inherited platelet functional defects include abnormalities of platelet surface proteins, abnormalities of platelet granules, and enzyme defects. The major surface protein abnormalities are thrombasthenia ( Glanzmann thrombasthenia ) and Bernard- Soulier syndrome. the platelet glycoprotein IIb / IIIa (GP IIb / IIIa ) complex is either lacking or present but dysfunctional. This defect leads to faulty platelet aggregation and subsequent bleeding. Transfusion of normal platelets is required for bleeding in these patients.

48. Qualitative Platelet Defects Impaired platelet function often accompanies thrombocytopenia but may also occur in the presenced of a normal platelet count.

49. Management of periodontal patients with bleeding disorders Pre-operative precautions A detailed medical history must include the following Previous hemorrhagic episodes after trauma or surgery, or even spontaneous bleeding. Family history regarding hereditary bleeding disorders. Current illnesses, such as hepatic and renal failure, and a list of medications interfering with hemostasis, such as nonsteroidal anti-inflammatory drugs and antibiotics. Anticoagulation medications, such as coumarin , heparin, aspirin, clopidogrel , and ticlodipine . Pre-operative care of patients on anticoagulant therapy with coumarin involves the continuation, reduction or withdrawal of the medication. The decision should be based on the international normalized ratio value, the invasiveness and extent of dental procedure, current illnesses and medications ( Scully C, Wolff A. 2002 ).

50. When the international normalized ratio is<<3.5, periodontal surgical procedures can be carried out on these patients in a dental office ( Little JW et al 2002, Lockhart PB et al 2003, Scully C et al 2002) . When the international normalized ratio is >3.5, the anticoagulation regimen has to be adjusted. A safe approach entails reduction of the coumarin dose 2–3 days before the procedure and repetition of international normalized ratio testing the morning of the procedure to ensure that the value is <4 ( Little JW et al 2002, Lockhart PB et al 2003, Scully C et al 2002 ). International normalized ratio therapeutic levels for most medical conditions range between 2.5 and 3.5 ( Beirne OR, Koechler JR 1996 ). Extensive and invasive periodontal surgical procedures in such patients should be performed in a hospital setting, and intravenous unfractionated heparin should be given as a substitute for coumarin 4–6 hours before the surgical procedure ( Scully C et al 2002 ). Patients taking aspirin should discontinue the medication at least 3 days, and up to 7 days, before the surgical procedure .

51. The dental professional may decide if modification of the anticoagulant regimen will place the patient at risk for a thromboembolic event . In addition, the care of patients with bleeding disorders must be placed into new perspective. Preventive dental care for patients with known bleeding disorders has to be intensive and should include regular dental visits, frequent professional tooth cleanings, oral hygiene reinforcement, fluoride supplements and mouthrinses , a low-sugar diet and annual radiographic examination. Continued efforts to prevent dental diseases, and arresting dental diseases at the initial stage, eliminate the need for invasive dental procedures and reduce the risk of associated prolonged bleeding. Patients with diagnosed congenital bleeding disorders should consult their hematologist before any treatment is rendered.

52. Intra-operative actions minor surgery, involving soft tissues, can be performed with platelet counts as low as 30,000/ μl (Henderson JM et al 2001 ). In mild and moderate inherited coagulopathies, desmopressin or 1-desamino-8-D arginine vasopressin can be useful. Professional cleaning, and scaling and root planing , can be safely performed with the use of local antifibrinolytic mouthwash, such as tranexamic acid or epsilon aminocaproic acid ( little JW et al 2002 )). Regional block anesthesia must be avoided. Another way to prevent excessive bleeding is the meticulous handling of soft tissues. Creating a conservative flap design and minimizing flap elevation are key points. Application of pressure for 10 minutes with moistened gauze on the flap has been suggested ( Scully C , Wolff A 2002 ). At the end of surgery, patients susceptible to bleeding are instructed to bite on a moistened gauze, or gauze soaked with the hemostatic agent, for 30 minutes.

53. After 30 minutes, the gauze is removed and the surgical area is observed for oozing. If bleeding occurs, additional measures are initiated. The surgical area is re-entered and the bleeding source is identified. Electrocautery and laser are used to control bleeding in the soft tissues. When oozing arises from hard tissues, bone burnishing and bone wax are the treatments of choice. There are a number of commercially available local hemostatic agents that enhance clot stabilization. These include : absorbable gelatin; absorbable collagen; microfibrillar collagen and collagen dressings ; oxidized regenerated cellulose , thrombin, tranexamic acid and epsilon- aminocaproic acid ; fibrin glue; and platelet-rich plasma . Collagen, gelatin and cellulose products provide the scaffold for platelets to adhere to one another and form the platelet plug

54. Postoperative measures Rinsing is prohibited on the day of surgery and the healing site must be left undisturbed. The use of antifibrinolytic mouthwash is highly recommended the day after periodontal treatment. The regimen may comprise rinsing with 10 ml of 4.8–5%tranexamic acid solution, four times a day, for 2 minutes. The rinsing can be carried out over a period of 2–5 days and may be extended up to 8 days ( Franchini M et al 2005 ). Antibiotics, such as penicillin, erythromycin, tetracycline, metronidazole, cephalosporins , ampicillin and amoxicillin + clavulanic acid, potentiate the coumarin action ( Herman WW et al 1997, Scully C , Wolff A 2002 ). Acetaminophen can also interact with coumarin and its use must be limited to fewer than six tablets per week ( Scully C , Wolff A 2002 ).

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