Hemorrhage

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Hemorrhage

  1. 1. Hemorrhage Hemorrhage (Hema + Rrhage) means the escape of blood from a blood vessel.  The word hemorrhage is synonymous with bleeding.  Any damage to the vasculature leads to outflow of blood.  Blood carries oxygen & nutrients to the tissues and is vital for body functions. Loss of blood due to any reason beyond a certain point is potentially life threatening & may lead to exsanguinations. History Method for controlling hemorrhage  Ambroise pare’s (1510-1590) position in the evolution of surgery remains of supreme importance.  From 1536 until just before his death, pare was either engaged as an army surgeon, or performing surgery in civilian practice in Paris.  Other surgeons were using boiling oil as a means of cauterizing fresh gunshot wounds, Pare’s employment of a less irritating emollient of egg yolk, rose oil & turpentine brought him lasting fame & glory.  Among Pare’s important corollary observations was that in performing an amputation, it was more efficacious to ligate individual blood vessels than to attempt to control hemorrhage by means of mass ligation of tissue or with hot oleum.  Pare humbly attributed his success to patient’s god as noted in his famous motto, “Je le pansay, Dien le guerit,” that is “I treated him .god cured him.” 1
  2. 2. Types of hemorrhage I. 1) External hemorrhage- is one that is revealed outside or seen externally. 2)Internal hemorrhage- is one that is not seen from outside. o Also called as concealed hemorrhage • e.g.:- Bleeding peptic ulcer ruptured ectopic gestation, fracture of major bones, rupture of liver, spleen etc. • Sometimes concealed hemorrhage may be external hemorrhage. • e.g.:- Haematemesis or malaena from bleeding peptic ulcer, haematuria from ruptured kidney. II Acc. to the source of hemorrhage 1) Arterial hemorrhage- is one which comes from a ruptured artery -It is bright red color & is pulsative. 2) Venous hemorrhage- is one which comes from a vein.  Characterized by dark red color & flows out steadily instead of spurts  Very difficult to stop venous hemorrhage  Due to lack of valves in veins of the facial region & extensive communication, there is relatively more flow from veins as compared to other parts of body. 3) Capillary hemorrhage- is one in which hemorrhage occurs from capillaries.  Bright red in color & oozes rather than flows out & no bleeding point can be made out. 2
  3. 3.  Bleeding is not severe & is easily controlled by simple pressure with gauze pads.  In coagulation disorders, there can be extensive blood less from capillaries.  . III. According to the time of appearance 1) Primary hemorrhage- is one which occurs at the time of injury or operation.  Hemostatic mechanisms in the body attempt to stop the bleeding by formation of clot 2) Reactionary hemorrhage- is one which occurs within 24 hours of injury or operation.  In majority of cases it occurs within 4-6 hours.  Occurs due to dislodgement of blood clots or slipping of ligatures Mostly occurs due to rise of blood pressure when the patient recovering from anesthesia or shock & also occurs due to restlessness, coughing or vomiting which raises the venous pressure 3) Secondary hemorrhage- is one which occurs after 24 hours to 7-14 days of injury or operation.  This is usually due to infection. 4) Spontaneous bleeding- occurs without any provocation. E.g.:- In acquired (patients on oral hypoglycaemic agents- decreases platelet count) & hereditary coagulopathies. Causes of hemorrhage 1) Trauma to the vessel wall e.g.:- penetrating wound in the heart or great vessels, during labour etc. 3
  4. 4. 2) Spontaneous hemorrhage e.g.:- rupture of an aneurysm, septicaemia, bleeding deathesis, acute leukemia, pernicious anemia, scurvy. 3) Inflammatory lesions of the vessel wall e.g.:- bleeding from chronic peptic ulcer, typhoid ulcer, blood vessels transversing a tuberculous cavity in the lung, syphilitic involvement of the aorta, poly arthritis nodosa. 4) Neoplastic invasion e.g.:- hemorrhage following vascular invasion in carcinoma of tongue. 5) Vascular diseases- e.g.:- atherosclerosis. 6) Elevated pressure within the vessels e.g.:- cerebral & retinal hemorrhage in systemic hypertension. Effects of hemorrhage The effects of blood loss depend upon 3 main factors 1) The amount of blood loss 2) The speed of blood loss 3) The site of hemorrhage  The loss up to 20% of blood volume suddenly or slowly generally has little clinical effects because of compensatory mechanisms.  A sudden loss of 33% of blood volume may cause death, while loss of up to 50% of blood volume over a period of 24 hours may not be necessarily fatal.  Chronic blood loss generally produces an iron deficiency anemia, where as acute hemorrhage may lead to serious immediate consequences such as hypovolemic shock. 4
  5. 5. Clinical features of hemorrhage  Increased pulse rate, low blood pressure, increasing pallor, restlessness and deep signing respiration ( air hunger) are the typic features of acute blood loss.  Cold & clammy extremities, empty veins are also characteristically seen which the bleeding is continuing. Pulse rate & blood pressure should be measured ¼ or ½ hourly intervals when the patient is losing blood. Though fall of B.P is often noticed in case of hemorrhage, yet a normal B.P cannot exclude the diagnosis of hemorrhage. Often the B.P is maintained at normal level by peripheral vasoconstriction due to adlenergic release when the patient is still bleeding. Suddenly the B.P may fall abruptly with collapse & even death of the patient. Pulse rate is a better indicator of hemorrhage than B.P. usually with hemorrhage the pulse rate is increased, when the blood loss has been excessive the pulse becomes of low volume, which is classically known as thready pulse. Measuring of urine output is obligatory in patient who is losing blood. Urine output becomes low in patients suffering from hemorrhage & shock. Measurement of blood loss  It is often important to measure how much the patient has lost blood. This amount should always be replaced.  The blood loss detected by the methods is usually less than the actual loss because a considerable amount of plasma is lost into the interstitial tissues & a considerable amount of water is lost via lungs, from the wounds and by evaporation of sweat from the skin. This loss of plasma & water constitutes 5
  6. 6. approximately 20% more than the blood loss detected by various methods. The best method of detecting blood loss is by weighing swabs. The other methods are measurement of swelling in case of bleeding from fractures & measurement of blood clot in hemorrhage. 1) Weighing of swab  The swabs are weighed before they are used & they are weighed again after they are soaked with blood & thrown individually into a collecting basket.  The difference of weight is the amount of blood loss. 1gm=1ml of blood loss  It cannot give the actual amount of blood loss & it should be multiplied by a factor of 1 ½ in case of moderate operations. In case of longer operations the swab weighing total should be multiplied by a factor of 2. 2) Measurement of swelling in closed fractures In case of moderate swelling in closed fractures of the tibia, the blood loss is estimated at 1000 to 1500 ml. In moderate swelling in case of fractured shaft of femur, the estimated blood loss is about 1000 to 2000 ml. 3) Measurement of blood clot When the collected blood clots are kept in a pot & measured against a clenched fist of the patient, total blood clot of the size of the clenched fist is equal to 500ml of blood. Blood volume determinations Blood volume = red cell volume + plasma volume. Haematoceit reading gives the ratio of plasma to red cells. Firstly the plasma volume or the red cells volume is measured & from the haematocrit valve the total blood volume can be 6
  7. 7. determined the normal blood volume is about 80 ml of whole blood per kg body weight that means in case of an adult of normal structure the normal blood volume is about 5 to 6 liters. In certain pathological conditions this blood volume is increased e.g.:-chronic anemia & arterio-venous fistula. Hemoglobin level: - It is often considered as a good indication of hemorrhage. But it is practically not so. In the initial stage the hemoglobin level remains normal. It is only lowered after a few hours by haemodilution caused by movement of extra cellular fluid into the vascular space due to nature attempt to restore blood volume. Measurement of CVP: - Good method to detect loss of blood volume in hemorrhage. HEMOSTASIS & BLOOD COAGULATOIN The term hemostasis means prevention of blood loss. whenever a vessel is severed or ruptured,hemostasis is achieved by several mechanisms; 1. Vascular spasm. 2. Formation of platelet plug. 3. Formation of a blood clot as a result of blood coagulation. 4. Eventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently. Vascular constriction * Immediately after a blood vessel has been cut or ruptured, the trauma to the vessel wall itself causes the vessel to contract; this instantaneously reduces the flow of blood from the vessel rupture. 7
  8. 8. * The contraction results from nerve reflexes, local myogenic spasm, local humoral factors from the traumatized tissues &blood platelets. * For the smaller vessels platelets are responsible for much of the vasoconstriction by releasing the vasoconstrictor substance thromboxane A2. * The local vascular spasm can last for many minutes or even hours, during which time the processes of platelet plugging & blood coagulation can take place. Formation of the platelet plug If the vent is very small- & many very small vascular holes do develop throughout the body each day –it is often sealed by a platelet plug rather than by a blood clot. Characteristics of platelets Platelets in their cytoplasm contain active factors such as (1) Actin and myosin molecules, similar to those found in muscle cells, as will as still another contractile protein, thrombosthenin, that can cause the platelets to contract. (2) Residuals of both the endoplasmic reticulum and the golgi apparatus that synthesize various enzymes and especially store large quantities of calcium ions. (3)Mitochondria and enzyme systems that are capable of forming adenosine triphospahte and adenosine diphosphate (ADP). (4) Enzyme systems that synthesize prostaglandins, which are local hormones that cause many types of vascular and other local tissue reactions. (5)An important protein called fibrin-stabilizing factor (6) A growth factor that causes vascular endothelial cells, vascular smooth muscle cells and fibroblasts to multiply and grow thus causing cellular growth that helps repair damaged vascular walls. 8
  9. 9. * The cell membrane of the platelet is also important. On its surface is a coat of glycoproteins that repulses adherence to normal endothelium and yet causes adherence to normal endothelium and yet causes adherence to normal endothelium and yet causes adherence to injured areas of the vessel wall * Contains large amounts of phospholipids that play several activating roles at multiple points in the blood clotting process. Mechanism of platelet plug • When platelets comes in contact with the vascular surface, such as the collagen fibres in the vascular wall the platelets themselves immediately change their characteristics drastically. • They begin to swell they assumes irregular forms with numerous irradiating psuedopodes protruding from their surfaces • Their contractile routine contract forcefully and cause the release of granules that contain multiple active factors • They become sticky so that they adhere to collagen in the tissue and a protein called von willebrand factor that spreads throughout the plasma; • They secrete large quantities of ADP and their enzymes form thromboxane A2. the ADP and thromboxane inturn act on nearby platelets to activate them as well and the stickiness of these additional platelets causes them to adhere to the originally active platelets. • Therefore at the site any vent in a blood vessel wall, the damaged vascular wall or extra vascular tissue elicit activation of successively increasing numbers of platelets 9
  10. 10. that themselves attract more and more additional platelets, thus forming a platelet plug. Blood coagulation in the ruptured vessel • The third mechanism for hemostasis is formation of the blood clot. The clot begin to develop in 15 to 20 seconds if the trauma to the vascular wall has been severe and in 1 to 2 minutes if the trauma has been minor. • Activator substances from the traumatized vascular wall, from platelets, and from blood proteins adhering to the traumatized vascular wall initiate the clotting process. • Within 3 to 6 minutes after rupture of a vessel, if the vessel opening is not too large the entire opening broken end of the vessel is filled with clot. After minutes to an 10
  11. 11. hour, the clot retracts; this closes the vessel still further. 11
  12. 12. fibrous organization or Dissolution of the blood clot * Once a blood clot has formed, it can follow one of two courses (1) it can become invaded by fibroblasts, which subsequently form connective tissue all through the clot, or (2) 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 factors secreted by platelets). This continues to complete organization of the clot into fibrous tissue within about 1 to 2 weeks. Mechanism of blood coagulation Basic theory ** More than 50 important substances that affect blood coagulation have been found in the blood and in the tissue- some that promote coagulation, called procoagulation and others that inhibit coagulation called anticoagulation. ** Whether blood will coagulate depends on the balance b/w these 2 groups of substances. ** In the blood stream the anticoagulants normally predominant, so that the blood doesn’t coagulate while it is circulating in the blood vessels. But when a vessel is ruptured, procoagulants in the area of tissue damage become activated and override the anticoagulant and then a clot does develop. General mechanism All research workers in the field of blood coagulation agree that clotting takes place in 3 essential steps. 1) In response to rupture of the vessel or damage to the blood itself, a complex cascade of chemical reaction occurs in the blood involving more than a dozen 12
  13. 13. coagulation factors the net result is formation of a complex of activated substances collectively called prothrombin activator. 2) The prothrombin activator catalyzes the conversion of prothrombin into thrombin. 3) 4) The thrombin acts as an enzyme to convert fibrinogen into fibrin fibers that enmesh platelets, blood cells & plasma to form the clot. Conversion of prothrombin into thrombin ** After prothrombin activator has been formed as a result of rupture of a blood vessel or as a result of damage to special activator substances in the blood, the prothrombin activators in the presence of sufficient amount of calcium, causes conversion of prothrombin into thrombin. ** The thrombin in turn causes polymerization of fibrinogen molecules into fibrin fibers within another 10 to 15 seconds. ** Platelets also plays an important role in conversion of prothrombin into thrombin because much of the prothrombin receptors on the platelets that have already bound to the 13
  14. 14. damaged tissue. Then this binding accelerates the formation of still more thrombin from Prothrombin & Thrombin 14
  15. 15. ** Prothrombin is formed continually in the liver and it is continually being used throughout the body for blood clotting. If the liver fails to produce prothrombin in a day or so, the prothrombin concentration in the plasma falls too low to provide normal blood coagulation. ** Vitamin K is required by the liver for the normal formation of prothrombin as well as for formation of 4 other clotting factors. Therefore either lack of vitamin K or the presence of liver disease that prevents normal prothrombin formation can decrease the prothrombin level so low that a bleeding tendency results. Conversion of fibrinogen into fibrin- formation of the clot Fibrinogen: Because of their large molecular size, little fibrinogen normally leaks from the blood vessel into the interstitial fluids, and because fibrinogen is one of the essential factors in the coagulation process, interstitial fluids ordinarily don’t coagulate. When the permeability of the capillaries become pathologically increased, fibrinogen does leak into the tissue fluids in sufficient quantity to allow clotting of these fluids in much the same way that plasma and whole blood clot. Action of thrombin on fibrinogen to form fibrin * Thrombin is a protein enzyme with weak proteolytic capabilities. * It acts on fibrinogen to remove four low-molecular-weight peptides from each molecule of fibrinogen, forming a molecule of fibrin monomer that has the automatic capability to polymerize with other fibrin monomer molecules, thus forming fibrin. * Therefore many fibrin monomer molecules polymerize within seconds into long fibrin fibers that then constitutes the reticulum of the clot. 15
  16. 16. * In the early stages of this polymerization, the fibrin monomer molecules are held together by weak noncovalent hydrogen bonding, and the newly forming fibers are not cross linked with one another therefore the resultant clot is weak and can be broken apart with ease. * But then, another process occurs during the next few minutes that greatly strengthen the fibrin reticulum. This involves a substance called fibrin stabilizing factor that is normally present in small amounts in the plasma globulins but is also released from platelets entrapped in the clot. * Before fibrin stabilizing factor can have an effect on the fibrin fibers, it must itself be activated. The same thrombin that causes thrombin formation also activates the fibrin stabilizing factor. * Then this activated substance operates as an enzyme to cause covalent bonds b/w more &more of the fibrin monomer molecules, as well as multiple cross-linkages b/w adjacent fibrin fibres,thus adding tremendously to the 3 dimensional strength of the fibrin meshwork. The blood clot The clot is composed of a meshwork of fibrin fibres running in all directions & entrapping blood cells,platelets,&plasma.. The fibrin fibers also adhere to damaged surfaces of blood vessels; therefore the clot becomes adherent to any vascular opening &thereby prevents further blood loss. Clot retraction-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. 16
  17. 17. • The fluid expressed is called serum because all its fibrinogen and most of the other clotting factors have been removed in this way, serum differs from plasma. Serum cannot clot because it lacks these factors. * 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 is low. * Platelets entrapped in the clot continue to release procoagulant substances, one of which is fibrin stabilizing factor, which carses more and more cross linking bonds b/w the adjacent fibrin fibers. In addition, the platelets themselves contribute directly to clot contraction by activating platelet thrombosthenin, actin and myosin molecules, which are contractile proteins in the platelets and cause strong contraction of the platelet spicules attached to the fibuin. This 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 folge apparatus of the platelets. * As the clot retracts, the edges of the broken blood vessel are pulled together thus contributing still further to the ultimate state of homeostasis. 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: (1) by the extrinsic pathway that begins with trauma to the vascular wall and surrounding tissues and (2) by the intrinsic pathway that begins in the blood itself. In both the extrinsic and the intrinsic pathway, a series of different plasma proteins called blood-clotting factors play major roles. 17
  18. 18. Most of these are inactive forms of proteolytic eczymes. When converted to the active forms, their enzymatic actions cause the successive, cascading reactions of the clotting process. Extrinsic pathway for initiating clotting The extrinsic pathway for initiating the formation of prothrombin activator begins with a traumatized vascular wall or extra vascular tissues that come in contact with the blood. 1) Release of tissue factor. Traumatized tissue releases a complex of several factors called tissue factor or tissue thromboplastin. This is composed especially of phospholipids from the membranes of the tissues plus a lipoprotein complex that functions mainly as a proteolysis enzyme. 2) Activation of factor X- role of factor VII and tissue factor. The lipoprotein complex of tissue factor further complexes with blood coagulation factor VII and in the presence of calcium ions, acts enzymatecally on factor X to form activated factor X (Xa). 3) Effect of activated factor X (Xa) to form prothrombin activator- role of factor V. the activated factor X combines immediately with tissue phospholipids that are part of tissue factor or with additional phospholipids released from platelets as well as with factor V to form the complex called prothrombin activator. Within afew seconds, in the presence of calcium ions (Ca++), this splits prothrombin to form thrombin, and the clotting process proceeds as already explained. At first, the factor V in the prothrombin activator complex is inactive, but once clotting begins and thrombin activates factor V. this then becomes an additional strong accelerator of prothrombin activation. Thus in the final prothrombin activator complex, activated 18
  19. 19. factor X is the form thrombin activated factor V greatly accelerates this protease activity, and platelet phospholipids act as a vehicle that further accelerates the process. Note especially the positive feedback effect of thrombin acting through factor V, in accelerating the entire process once it begins. Intrinsic pathway for initiating clotting The second mechanism for initiating the formation of prothrombin activator and therefore for initiating clotting begins with trauma to the blood itself or exposure of the blood to collagen from a traumatized blood vessel of the blood to collagen from a traumatized blood vessel wall. 1) Blood trauma causes (1) activation of factor XII and (2) release of platelet phospholipids. Trauma to the blood or exposure of the blood to vascular wall collagen alters two important clotting factors in the blood: factor XII and the platelets. When factor XII is disturbed, such as by coming into contact with collagen or with a wettable surface such as glass, it takes on a new molecular configuration that converts it into a proteolytic enzyme called “activated factor XII”. Simultaneously, the blood trauma also damages the platelets because of adherence to either collagen or a wettable surface (or by damage inother ways), and this releases platelet phospholipids that contain the lipoprotein called platelet factor 3, which also plays a role in subsequent clotting reactions. 2) Activation of factor XI. The activated factor XII acts enzymatically on factor XI to activate this factor as well, which is the second step in the intrinsic pathway. This reaction also requires HMW (high molecular weight) kininogen and is accelerated by prekallikrein. 19
  20. 20. 3) Activation of factor IX by activated factor XI. The activated factor XI then acts enzymatic ally on factor IX to activate this factor also. 4) Activation of factor X- role of factor VIII. The activated factor IX, acting in concert with activated factor VIII and with the platelet phospholipids and factor 3 from the traumatized platelets, activates factor X. It is clear that when either factor VIII or platelets are in short supply, this step is deficient. Factor VIII is the factor that is missing in a person who has classic hemophilia, for which reason it is called antihemophilic factor. Platelets are the clotting factor that is lacking in the bleeding disease called thrombocytopenia. 5) Action of activated factor X to form prothrombin activator- role of factor V. This step in the intrinsic pathway is the same as the last step in the extrinsic pathway. That is activated factor X combines with factor V and platelet or tissue phospholipids to form the complex called prothrombin activator. The prothrombin activator in turn initiates within seconds the cleavage of prothrombin to form thrombin, thereby setting into motion the final clotting process, as described earlier. Role of calcium ions in the intrinsic and extrinsic pathways Except for the first two steps in the intrinsic pathway, calcium ions are required for promotion or acceleration of all the blood clotting reactions. Therefore in the absence of calcium ions, blood clotting by either pathway doesn’t occur. Interaction b/w the extrinsic & intrinsic pathways- summary of blood clotting initiation It is clear from the schemas of the intrinsic & extrinsic systems that after blood vessels rupture, clotting occurs by both pathways simultaneously. Tissue factor initiates the 20
  21. 21. extrinsic pathway whereas contact of factor XII and platelets with collagen in the vascular wall initiates the intrinsic pathway. An especially important difference b/w the extrinsic and intrinsic pathways is that the extrinsic pathway can be explosive; once initiated its speed of occurrence 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. Prevention of blood clotting in the normal vascular system- the intravascular anticoagulants Endothelial surface factors Probably the most important factors for preventing clotting in the normal vascular system are (1) the smoothness of the endothelial surface, which prevents contact activation of the intrinsic clotting system; (2) a layer of glycocalyx on the endothelium (glycocalyx is a mucopolysaccharide adsorbed to the surface of the endothelium), which repels clotting factors and platelets, thereby preventing activation of clotting; and (3) a protein bound with the endothelial membrane, thrombomodulin, which binds thrombin. Not only does the binding of thrombomodulin with thrombin slow the clotting process by removing thrombin, but the thrombomodulin thrombin complex also activates a plasma protein, protein C, that acts as an anticoagulant by inactivating activated factors V and VIII. 21
  22. 22. * When the endothelial wall is damaged its smoothness and its glycocalyx thrombomodulin layer are lost, which activates both factor XII and the platelets, thus setting off the intrinsic pathway of clotting * If factor XII and platelets come in contact with the subendothelial collagen, the activation is even more powerful. ANTITHROMBIN ACTION OF FIBRIN &ANTITHROMBIN III Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood. the most powerful of these are 1. the fibrin fibers that themselves are formed during the process of clotting & 2. an alpha-globulin called antithrombin III or antithrombin-heparin cofactor. * While a clot is forming, about 85-90 percent of the thrombin formed from the prothrombin becomes adsorbed to the fibrin fibers as they develop. * This helps prevent the spread thrombin into the remaining blood &therefore, prevents excessive spread of clot. * The thrombin that does not adsorb to the fibrin fibers soon combines with antithrombin III,which further blocks the effect of the thrombin on the fibrinogen &then also inactivates the thrombin during the next 12-20 min. HEPARIN * Heparin is another powerful anticoagulant. but its conc. in the blood is normally low, so that only under special physiologic conditions does it have significant anticoagulant effects. 22
  23. 23. * By itself, it has little or no anticoagulant property, but when it combineswith antithrombin III, the effectiveness of antithrombin III in removing thrombin increases by a hundredfold to a thousandfold and thus it acts as an anticoagulant. * Therefore, in the presence of excess heparin, the removal of free thrombin from the circulating blood by antithrombin III is almost instantaneous. * The complex of heparin and antithrombin III removes several other activated coagulation factors in addition to thrombin, further enhancing the effectiveness of anticoagulation. The other includes activated factors XII, XI, IX and X. * Heparin is produced by mast cells & basophiles. Lysis of blood clots-plasmin • The plasma proteins contain a euglobulin called plasminogen (or profibrinolysin) that when activated, becomes a substance called plasmin (or fibrinolysin). • Plasmin is a proteolytic digestive enzyme of pancreatic secretion. Plasmin digests fibrin fibers as well as other protein coagulants such as fibrinogen, factor V, factor VIII, prothrombin and factor XII. • Therefore, whenever plasmin is formed it can cause lysis of the clot by destroying many of the clotting factors, thereby sometimes even causing hypocoagulability of the blood. Activation of plasminogen to form plasmin: then lysis of clots. • When a clot is formed, a large amount of plasminogen is trapped in the clot along with other plasma proteins. This will not become plasmin or cause lysis of the clot until it is activated. • The injured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator (t-(PA) that a day or so later, after the 23
  24. 24. clot has stopped the bleeding eventually converts plasminogen to plasmin, which in turn removes the remaining blood clot. • In fact many small blood vessels in which the blood flow has been blocked by clots are reopened by this mechanism. • Thus, an especially 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. Clinical evaluation of the bleeding patient HISTORY a) Any personal or family history of a bleeding tendency b) Bleeding problems after surgery or dental extraction. c) Bleeding problems after trauma d) Medication that cause bleeding -Aspirin,anticoagulants,long term antibiotic therapy e) Presence of illness that may have associated bleeding problems-leukemia,liver disease,hemophilia,congenital heart disease,renal disease f) Spontaneous bleeding from nose,ears,mouth,and so on. Physical examination  Check for adenopathy, splenomegaly or hepatomegaly  Assessment of the skin & mucosal surface 24
  25. 25.  Bleeding into superficial skin & soft tissues usually such as small capillary hemorrhage ranging from petechia to ecchymoses characteristic of abnormalities of the vessels or platelets  Hemorrhage into synovial joints is diagnostic of a severe coagulation disorder. Laboratory tests for screening Majority of defects of hemostasis can be screened by 4 basic tests. 1. Bleeding time:  Sensitive measure of platelet function  Normal bleeding time is less than 10 minutes  Prolonged in thrombocytopenia, von wille brand’s disease & platelet dysfunction 2. Platelet count  Normal platelet count is 1,50,000 to 4,50,000 per ml of blood  When count becomes 50,000 to 1,00,000 per ml, there is mild prolongation of bleeding time, so that bleeding occurs after severe trauma or surgery.  < 50000 per ml results in easy bruising manifests as petechia & ecchymoses during trauma or surgery.  < 20,000 per ml – spontaneous bleeding may be intracranial or any other internal bleeding.  Minor oral surgical procedure can be safely done, if platelet count is above 80,000 to 1,00,000 per ml, otherwise platelet needs transfusion of platelet rich plasma. 25
  26. 26. 3. Prothrombin time (PT)  Screens the extrinsic limb of coagulation pathway factor V, VII,X & factor I, II & V of the common pathway  Normal PT is 12-14 second  Prolonged in patients on warfarin anticoagulant therapy, vitamin K deficiency of factor V, VII, X, prothrombin & fibrinogen  As a general guideline for dental procedures, the PT should be less than 1 ½ of the control value. 4. Partial thromboplastin time (PTT)  Screens the intrinsic limb of coagulation pathway & tests for the adequacy of factor I, II, V of the common pathway  PTT is prolonged in haemophilic patients.  Normal PTT is < 45 seconds. If both PT & PTT are of prolonged, then factor II, V, X or vitamin K deficiency & liver disease are suspected. Management of hemorrhage  Surgical bleeding, even when alarmingly excessive, is usually caused by ineffective local hemostasis.  The goal of local hemostasis is to prevent the flow of blood from incised or transected blood vessels. 26
  27. 27. This may be accomplished by interrupting the flow of blood to the involved area or by direct closure of the blood vessel wall defect . Rest: -  Absolute rest is vital as far as the treatment of hemorrhage is concerned. Restlessness causes more bleeding.  Some sedatives & analgesics may be prescribed to provide rest to the patient.  Morphine is a good sedative & given 25 mg IV/IM.  Morphine is contraindicated when there is respiratory depression in head injuries, in children & in very old individuals where chloral hydrate is preffered.  Sedative may be prescribed along with morphine. Short acting temazepam & benzodiazepam may sense. The techniques may be classified as mechanical, thermal or chemical. 1) Mechanical procedure 1) Pressure  The oldest mechanical device to effect closure of the bleeding point is by pressure application.  When pressure is applied to an artery proximal to an area of bleeding, profuse bleeding is reduced, permitting more definitive action. 27
  28. 28.  Pressure should be applied directly over the bleeding site for at least 5 minutes.  The obvious disadvantage of digital pressure is that it cannot be used for a long period.  In case of oozing from bone, bone wax may be used. 2) Hemostat: - (artery forceps)  The hemostat also represents a temporary mechanical device to stem bleeding.  In smaller & non critical vessels, the trauma & adjacent tissue necrosis associated with the application of a hemostat are of little consequence.  These minor disadvantages are weighed by the mechanical advantage that the instrument offers to subsequent ligation. 3) Ligature  Replaces the hemostat as a permanent method of effecting hemostasis in a single vessel  When a large vessel has to be tied 3-0 non absorbable material is preferred.  Smaller vessels can be ligated with 3-0 catgut or polygalactin.  For large arteries with pulsation and longitudinal motion, transfixion suture to prevent slipping is indicated.  The T. adventitia & T. media constitute the major holding forces within the walls of large vessels and therefore multiple fine sutures as preferable to fewer larger sutures. 4) Embolization of the vessels 28
  29. 29.  Vessels that are usually investigated for treatment of oral & perioral lesions include the facial, lingual, transverse facial & internal maxillary arteries.  After the individual vessels are identified, contrast media is injected via the lesions are completely mapped angio graphically, emoblization of bleeding vessel can be carried out.  Agents used for embolization are steel coils, polyvinyl alcohol foam, gel foam, silicon spheres & methyl methacrylate. 2) Thermal agents I. Cautery  Heat achieves hemostasis by denaturation of proteins which results in coagulation of large areas of tissue.  In cauterization, heat is transmitted from the instrument by conduction directly to the tissues.  Even dental burnisher like instrument can be directly heated over a flame & applied directly to the bleeding point in the oral cavity. II. Electrosurgery  In electro surgery, heating occurs by induction from an alternating current source. Advantage: - saves time. Disadvantages: - burning smell & smoke during application.  Cannot control hemorrhage from the large vessels.  Certain anesthetic agents cannot be used with electrocautery because of the hazard of explosion. III. Cooling 29
  30. 30.  Direct cooling with iced saline is effective & acts by increasing the local intra vascular hematocrit & decreasing blood flow by vasoconstriction.  Extreme cooling that is cryogenic surgery has been applicable particularly in gynecology & neurosurgery.  Temperatures ranging between -20 to -180C are used and at temp -20C or below, the tissue capillaries, small arterioles and venules undergo cryogenic necrosis. IV. Argon-beam coagular  New form of electro cautery & more effective than electrocautery  In this, coagulator monopolar current is transmitted to tissues through the flow of argon gas.  This allows bleeding from vessels that are smaller than 3mm in diameter to be controlled without the use of hemostat or ligatures.  The tip of the coagulator is held approximately app.1cm from tissue.  A flow of argon gas clears the surgical site of fluids to allow current to be focused directly on tissue, with reduced carbonization.  There is formation of 1 to 2mm of Escher that covers the bleeding surface & remains attached to the tissues with fewer tendencies to rebleed.  There are possibilities of gas embolism, as there is stream of gas in direct contact with tissues. This risk can be eliminated by not placing hand piece tip in direct contact with tissues. V. Lasers  Results in bloodless surgery as there effectively coagulate the small blood vessels during cutting of tissues. 30
  31. 31. 3) Chemical agents- local & systemic Local agents  Chemical agents vary in their hemostatic action. Mechanism of action: They may act by any of the following properties a) Vasoconstriction property b) Coagulant property c) Hygroscopic property which increases their bulk and aid in plugging disrupted blood vessels. 31
  32. 32. Systemic agents 1) Whole blood  When there is excessive blood loss due to hemorrhage & there are symptoms of hypovolemia shock, whole blood transfusion may be indicated. History of blood transfusion 32
  33. 33.  In June of 1667, jean-Baptiste Denis and a surgeon, Emmerez, transfused blood from a sheep into a 15 year old boy who had been bled many times as treatment for fever  The patient apparently improved and a successful experience was reported simultaneously in another patient.  Because of two subsequent deaths associated with transfusion from animals to humans, criminal charges were brought against Denis.  In April 1668, further transfusions in humans were forbidden unless approved by the faculty of medicine in Paris.  It was not until the 19th century the human blood was recognized as the only appropriate replacement.  In 1900, Landsteiner and his associates introduced the concept of blood grouping & identified the major A, B, & O group. In 1939, the Rh. group was recognized. Collection of blood for blood transfusion  Before collecting blood from an individual or donor, make sure that the donor is not suffering from any disease which may be transmitted into the blood e.g.: Hepatitis & AIDS.  The donor lies down on a bed. A sphygmo-manometer cuff is applied to the upper arm & in inflated to a pressure of 80mm Hg.  0.5ml local anaesthetic solution is injected subcutaneously in the antecubital fossa through which 15 gauge needles is introduced into medium cubital vein. 33
  34. 34.  The needle is connected to a plastic tube which is attached to a plastic bag which forms a sterile unit.  Blood from the donor is allowed to come out & run into the sterile bag which already contains 75ml of anticoagulant solution.  During collection, blood is constantly mixed with the anticoagulant solution to prevent clotting.  A specimen of blood is sent for grouping and cross matching. About 410ml is taken in a single bag. Two types of anticoagulant solutions are usually used to mix with the donor blood. 1) CPD solution- contains tri sodium citrate (dehydrate), citric acid (mono hydrate), sodium di hydrogen phosphate (mono hydrate) and dextrose mixed with water. 2) CPDA-1 solution- with the above mentioned solution adenosine is added to increase the storage life of blood. Blood storage  Stored in blood bank in special refrigerator at controlled temperature of 4 degree centigrade (6-2C)  If blood is allowed to come in contact with higher temperature, there is danger of transmitting infection.  During storage, the RBC loses their ability of release oxygen to the tissues of the recipient with in 7 days.  WBC is rapidly destroyed.  Platelets are destroyed.  Clotting factors e.g.: factor V, VIII & are also destroyed quickly.  Factors II, VII, IX & XI are stable in banked blood. 34
  35. 35.  Shelf life of stored blood in CPD solution is about 3weeks & with CPD-1, 5 weeks. Besides whole blood, packed red cells are also transfused in certain conditions. Packed red cells: -Whole blood is centrifuged at 2000 to 2500g for 15 to 20minutes or if the stored blood is allowed to stay idle so that the supernatant plasma is taken off and the blood sediment is used for packet cells. Transfused specially in patients with chronic anemia Other blood substitutesDivided into 2 groups 1) Plasma & its derivatives 2) Synthetically prepared various solutions 1) Plasma & its derivatives Plasma can be separated from the packed red cells after centrifugation at 2000 to 2500g for 15 to 20 minutes and also by allowing the blood to stay idle for sometime so that the supernatent plasma is taken off leaving packed red cell sediments. Fresh frozen plasma: Plasma removed from fresh blood, which is obtained with in 4 hours, in rapidly frozen by immersing solid CO2 & ethyl alcohol mixture. Such plasma is stored at -20C. This process preserves all the coagulation factors, particularly factors V and VIII, & useful in the treatment of coagulation deficiencies in liver disease ,in haemophilea, Christmas disease, in defibrination cases, & vitamin K deficiency. 35
  36. 36. 2) Platelet rich plasma  Suitable for patients suffering from thrombocytopenic purpura  Prepared by slow centrifugation of fresh whole blood (at the rate of 150 to 200 g for 15-20 minutes)  One unit of PRP raises the platelet count approximately by 7,000-10,000 per ml. Platelet concentrate  It is prepared from platelet rich plasma by centrifugation at the rate of 1500g for 20minutes. This is further acidified to a pH of 6.5.  The platelet remains active in vitro for 48hours. If the platelet concentrate is stored frozen, its effectiveness may be extended to many months of storage.  Both platelet rich plasma & platelet concentrate are used in cases suffering from thrombocytopenic purpura. 3) Fibrinogen  It is prepared by organic liquid fractionation of plasma.  It is stored in dried form & before using it is made soluble with distilled water.  Used in congenital afibrinogenaemia & in DIC. 4) Albumin  Prepared by repeated fractionation of plasma by organic liquids and then followed by heat treatment.  May be stored for several months in liquid form at 4C  Main advantage is that it is free from the danger of transmission of serum hepatitis. 36
  37. 37.  Used as a volume expander in patients who cannot tolerate a sodium load (cirrhotic patients) & in patients with severe albumin loss e.g.: following severe burn & in nephritic syndrome.  Disadvantage: - expensive. 5) Cryoprecipitate  If the frozen plasma is allowed to bring at a temperature of 4C, it will be divided into a white glutinous precipitate & supernatant plasma. The glutinous precipitate is known as cryoprecipitate.  It is usually stored at -40C  Rich source of factor VIII, so used for in the treatment of hemophilic patients.  Also contains a good amount of fibrinogen & may be used in conditions of hyofibrinogenaemia. B. Synthetically prepared various solution 1) Dextran  The bacterium leuconostoc mesenteroides produces this polysaccharide compound to which a yeast extraction is added.  This solution induces roulcaux formation of red cells. It also interferes with the platelet function, so that it may induce abnormal bleeding. So this solution should not be used more than 1000ml. It also interferes with blood grouping & cross matching, so blood sample for grouping & cross matching should be drawn before introducing this solution.  Used to restore plasma volume, in cases of DIC 37
  38. 38. 2) Gelatin  Less effective than dextran as plasma volume expander only 30% of this solution remains in the intravascular compartment after 4hours of infusion. 3) Hydroxyl ethyl starch (HES)  Second to dextran in its efficiency as a plasma volume expander 4) Fluorocarbons  Its main efficacy is that it can bind & release oxygen rather than merely passively transporting dissolved oxygen. It is considered to be a red cell substitute. Main difficulty is that there is considerable fall in partial pressure of oxygen very quickly. In order to maintain adequate arterial oxygen content the patient should be kept in hyperbaric environment. CLASSIFICATION OF BLEEDING DISORDERS: 1. Nonthrombocytopenic purpuras • Vascular wall alteration (1) Scurvy (2) infections (3) Chemicals (4) Allergy • Disorders of Platelet Function (1) Genetic defects (Bernard-Soulier Disease) ( 2) Drugs a).Aspirin b)NSAIDS c) Alcohol d) Beta-lactum Antibiotics e) Penicillin f) Cephalosporins 38
  39. 39. (3) Allergy (4) Autoimmune disease (5) Uremia 2. Thrombocytopenic purpuras • Primary-Idiopathic • Secondary ; (1) Chemicals (2) Physical agents (radiation) (3) Systemic diseases (leukemia) (4) Metastatic cancer to bone (5) Splenomegaly • (6) Drugs a) Alcohol . . b) Thiazide diuretics c) Estrogens d) Gold salts (7) Vasculitis (8) Mechanical prosthetic heart valves (9) Viral or bacterial infections 3. Disorders of coagulation • Inherited (1) Hemophilia A (deficiency of factor VIII) (2) Hemophilia B (deficiency of factor IX) (3) von Willebrands disease (secondary factor VIII deficiency) (4) Others. . . • Acquired (1) Liver disease (2) Vitamin deficiency a) Biliary tract obstruction b) Malabsorption c) Excessive use of broad spectrum antibiotics (3) Anticoagulation drugs 39
  40. 40. a) Heparin b) Coumarin . c)Aspirin and NSAIDS (4) DIC (5) Primary fibrinogenolysis . INHERITED COAGULATION DISORDERS: The most important inherited bleeding disorders in terms of prevalence and severity are haemophilia A and B (Christmas disease) and von Willebrand's disease. Many of the defects present a hazard to surgery and to local anaesthetic injections, but in general the teeth erupt and exfoliate without problems, and non-invasive dental care is safe. HAEMOPHILIA A: • Haemophilia A is the most common and best-known clotting defect, with a prevalence of about 5 per 100 000 of the population. • It is about 10 times as common as haemophilia B except in some Asians, where frequencies are almost equal. • Inherited as a sex-linked recessive trait, haemophilia affects males. A family history can, however, be obtained in only about 65 per cent of cases. • All daughters of an affected male are carriers but sons are normal. Sons of carriers have a 50:50 chance of developing haemophilia while daughters of carriers have a 50:50 chance of also being carriers. • Haemophilia A is due to defective Factor VIII (antihaemophilia factor, AHF). This is a glycoprotein of several components, including Factor VIHC (procoagulant that participates in the clotting cascade), VIIIR:Ag (von Willebrand factor, which binds to platelets and is the carrier for Factor VIIIC) and VIIR:RCo (ristocetin cofactor, which supports platelet aggregation). In haemophilia A only Factor VIIIC is reduced. CLINICAL FEATURES; • Haemophilia typically becomes apparent in childhood when bleeding into muscles or joints (Hemarthrosis) follows injuries. • Abdominal haemorrhage may simulate an acute abdomen 40
  41. 41. • Bleeding after dental extractions is sometimes the first or only sign of mild disease. • Bleeding into the cranium, bladder and other sites can cause severe or fatal complications. COMPLICATIONS • Haemorrhage in hemophiliacs is dangerous either because of loss of blood, or because there may be damage to joints, muscles and nerves, or pressure on vital organs if haemorrhage is internal. • Thus compression of the larynx and pharynx following haematoma formation in the neck can be fatal. • Dental extractions or deep lacerations are followed by persistent oozing for days or weeks arid in the past have been fatal. The haemorrhage cannot be controlled by pressure and, although clots may form in the mouth, they fail to stop the bleeding. • The characteristic feature of bleeding in haemophilia is that it seems to stop immediately after the injury (as a result of normal vascular and platelet response) but, after an hour or more, intractable oozing or rapid blood loss starts and persists. The severity of bleeding is dependent on two main factors: i 1. The level of Factor VIIIC activity: The severity of the disease is variable but correlates well with the Factor VIII level of the plasma. Normal plasma contains 1 unit of Factor VIII per ml, a level defined as 100 per cent. 2. The severity of trauma: Some very mild haemophiliacs may not bleed excessively even after a simple dental extraction, so that the absence of post-extraction haemorrhage cannot always be used to exclude haemophilia. Most will, however, bleed excessively after more traumatic surgery such as tonsillectomy. 41
  42. 42. Severity of Haemophilia: %Factor VIII Severe < 1 Moderate 1-5 Mild >5-25 Normal >25 Diagnosis and management of haemophilia A: , The typical findings in haemophilia can be summarized as follows: 1. Prolonged activated partial thromboplastin time (APTT). , ,.,:. 2. Normal prothrombin time (FT). • . : 3. Normal bleeding time. 4. Low Factor VIHC but normal VIIIR:Ag (von Willebrand factor) and R:RCo (ristocetin cofactor). . ...... *Factor VIII assay is required as even the APTT may be normal in mild haemophilia. If bleeding starts or is expected, treatment consists of replacement of the missing clotting factor, rest and often the use of antifibrinolytic agents. * Rarely, von Willebrand's disease may mimic haemophilia. The history may help to distinguish them but laboratory testing is essential. * Factor VIII must be replaced to a level adequate to ensure haemostasis. Some years ago this was achieved with fresh plasma, or fresh frozen plasma, cryoprecipitate or fractionated human factor concentrates obtained from pooled blood sources, but these had, and may still occasionally have, the potential to carry blood-borne pathogens such as hepatitis viruses, HIV and various herpes viruses. * Porcine Factor VIII and genetically engineered Factor VIII have been considerable advances. Regular prophylactic replacement of Factor VIII (antihaemophiliac globulin, AHF) is used when possible but necessitates daily injections. * AHF is also in short supply and expensive, and its use may be complicated by antibody formation or viral infections but heat treatment should inactivate HIV that might have been 42
  43. 43. missed in the screening of donors. Increasing reliance is therefore placed on desmopressin and tranexamic acid. Replacement therapy: * Human freeze-dried Factor VIII concentrate (Factor VIII fraction, dried) is used when the deficiency is sufficiently severe. This preparation is stable for one year at 4 °C but once reconstituted should be used without delay. * New recombinant Factor VIII is now available. In milder cases (Factor VIII levels within 5-25 per cent of normal) desmopressin and tranexarnic acid may be satisfactory and are increasingly used. Haemophilia and vonWillebrands Disease: Dental management in haemophilia A: Difficulties in the management of haemophiliacs may include: 1. Dental neglect necessitating frequent dental extractions. 2. Trauma, surgery and subsequent haemorrhage. 3. Factor VIII inhibitors. 4. Hazards of anaesthesia, especially nasal intubation, and intramuscular injections. 5. Risks of hepatitis, and liver disease. 6. HIV infection. 7. Aggravation of bleeding by drugs. 8. Anxiety. 9. Drug dependence as a result of chronic pain. Preventive dental care: Education of patient or parents, and preventive dentistry, should be started as early as possible. Dental neglect is common and can lead to serious consequences. Dental extractions are still a major problem for haemophiliacs The use of fluorides, fissure sealants, dietary advice on the need for sugar restriction and regular dental inspections from an early age are crucial to the preservation of the teeth. Prevention of periodontal disease is also imperative. Comprehensive dental assessment is needed at the age of about 12-13, to plan for the future and to decide how best to forestall difficulties resulting from overcrowding or misplaced third molars or other teeth. 43
  44. 44. ' Surgery and postoperative haemorrhage: Dental extractions and surgery are dangerous for haemophiliacs. Surgery should therefore be carefully planned to avoid complications. All necessary surgery (and other dental treatment) should of course be performed at one operation. Haemophiliacs require the care of specialists of many disciplines and should therefore be treated in Haemophilia Reference Centers, or associated units. Haemophilia cards are issued to confirmed haemophiliacs and give details of the diagnosis and the Centre from which advice can be obtained. Radiographs should be taken for any unsuspected disease and to assess whether further extractions might prevent future trouble. Injections: • Local anaesthesia should be avoided in the absence of Factor VIII replacement. • Regional (inferior dental or posterior superior alveolar) blocks or injections in the floor of the mouth must not be used since they can cause haemorrhage which, by allowing blood to track down to cause airway obstruction, can be life-threatening. Rarely, even submucosal infiltrations have caused widespread haematoma formation, but Intraligamentary injections may be safe. Infiltration anaesthesia may be used with caution and is adequate for conservative work in children, but lingual infiltration must be avoided. • If factor replacement therapy has been given, regional anaesthesia can be used, provided the Factor VIII level is maintained above 30 per cent, but infiltration is still preferable. Intravenous midazolam or relative analgesia can be used. • Intramuscular injections should be avoided unless replacement therapy is being given, as they can cause large haematoma. Oral alternatives are in any case satisfactory in most instances. Conservative dentistry: *Conservative treatment of the primary dentition and sometimes of the permanent dentition may be carried out without anaesthesia. 44
  45. 45. * If conservative treatment is not tolerated without anaesthesia, papillary or intraligamentary infiltration may achieve sufficient analgesia and is unlikely to cause serious bleeding. * Soft tissue trauma must be avoided and a matrix band may help prevent gingival laceration. However, care must be taken not to let the matrix band cut the periodontal tissues and start gingival bleeding. * A rubber dam is also useful to protect the mucosa from trauma but the clamp must be carefully applied. * High speed vacuum aspirators and saliva ejectors must be used with caution in order to avoid production of haematomas. Trauma from the saliva ejector can be minimized by resting it on a gauze swab placed in the floor of the mouth. Endodontics: *Root canal treatment may obviate the need for extractions and can usually be carried out without special precautions other than care to avoid reaming through the apex. * Topical application of 10 per cent cocaine to the exposed pulp is the choice for vital pulp extirpation. However, in severe haemophilia, bleeding from the pulp and periapical tissues can be persistent and troublesome. Periodontal treatment: In all but severe haemophiliacs scaling can be carried out under antifibrinolytic cover. Periodontal surgery necessitates factor replacement. Orthodontics: There is no contraindication to the movement of teeth in haemophilia. However, there must be no sharp edges to appliances, wires etc., which might traumatize the mucosa. Minor surgery: *Endotracheal intubation for general anaesthesia may cause bleeding from nasal trauma and is dangerous in unprepared patients, but since replacement therapy has to be given for the surgical procedure, intubation can be carried out. * An oral latex cuffed endotracheal tube is recommended to minimize trauma to the nasal and trachea lining. The possibility of anaemia due to earlier blood loss must also be remembered if general anaesthesia is contemplated. * A Factor VIII level of between 50 and 75 per cent is required for dental extractions. AHF may also need to be given postoperatively but many patients can be managed with antifibrinolytic agents given during the subsequent 10 days. If oral bleeding recurs 45
  46. 46. postoperatively, Factor VIII must be given. Some advise the administration of a further single dose of Factor VIII as a routine on the fourth or fifth postoperative day. However, this should be unnecessary if adequate Factor VIII has been given preoperatively. *Antifibrinolytics significantly reduce Factor VIII requirements. Tranexamic acid (Cyklokapron) is used in a dose of 1 g (30 mg/kg) orally, four times daily starting 24 hours preoperatively. Antifibrinolytics must not be used systemically where residual clots are present, for example in the urinary tract or intracranially. In haemophiliacs, the urine should therefore be examined preoperatively for haematuria. * Tranexamic acid used topically significantly reduces bleeding. Ten ml of a 5 per cent solution used as a mouth rinse for 2 minutes, four times daily for 7 days, is recommended. This solution can be made up by diluting 10 per cent tranexamic acid solution with sterile water. * Desmopressin (deafflino-8-D arginine vasopressin: DDAVP) is a synthetic analogue of vasopressin which induces the release of Factor VIIIC, von Willebrand's factor (vWF) and tissue plasminogen activator (tPA) from storage sites in endothelium. Given as an intravenous infusion (0.3-0.5 ug/kg just before surgery, and repeated 12 hourly if necessary for up to 4 days), desmopressin can temporarily correct the haemostatic defect in mild haemophilia. * Desmopressin may be useful for patients with Factor VIII inhibitors, and is also increasingly widely used, as mentioned earlier, for the management of mild haemophiliacs for such purposes as extractions. It is now available for subcutaneous or intranasal use when doses of 300 mg appear as effective as 0.2 mg/kg i.v. As desmopressin also causes release of plasminogen activator, tranexamic acid should also be given. * Desmopressin may cause facial flushing and slight tachycardia but the chief adverse effect is tachyphylaxis - declining response on repeated injection. Local measures: are also important to protect the operation area and minimize the risk of postoperative bleeding. • Thus surgery should be carried out with minimal trauma to both bone and soft tissues, and careful mouth toilet postoperatively is also essential. • Suturing (though theoretically unnecessary) is desirable to stabilize gum flaps and to prevent postoperative disturbance of wounds by eating. Non-resorbable sutures are preferred and should be removed at 4-7 days. Suturing carries with it the risk, if 46
  47. 47. there is postoperative bleeding, of causing blood to track down towards the mediastinum with danger to the airway. However, such an eventuality is an indication of inadequate preoperative replacement therapy, although complications of this sort can result from the presence of Factor VIII inhibitors when postoperative haemostasis is less predictable. • In the case of difficult extractions, when mucoperiosteal flaps must be raised, the lingual tissues in the lower molar regions should preferably be left undisturbed since trauma may open up planes into which haemorrhage can track and endanger the airway. The buccal approach to lower third molars is therefore safer. Minimal bone should be removed and the teeth should be sectioned for removal where possible. • The packing of extraction sockets is unnecessary if replacement therapy has been adequate but some advice the packing of a small amount of oxidized cellulose soaked in tranexamic acid into the depths of the sockets. • Acrylic protective splints are rarely used now, in view of their liability to cause mucosal trauma and to promote sepsis, but they may be needed in certain sites such as the palate. Local haemostasis can be aided by collagen, Gelfoam or Surgicel inserted into extraction sockets, and by cyanoacrylate or fibrin glues. Prevention of infection: • Antimicrobials such as oral penicillin V 250 mg four times daily should be given postoperatively for a full course of 7 days to reduce the risk of secondary haemorrhage. Infection also appears to induce fibrinolysis. Postoperatively, a diet of cold liquid and minced solids should be taken for up to 10 days. Care should be taken to detect haematoma formation which may manifest itself by swelling, dysphagia or hoarseness. The patency of the airway must always be ensured. Major surgery: • Before major surgery the patient is assessed by haemostatic screening (AFTT, PT, and platelet) count), Factor VIII assay, specific antibody test, fibrinogen estimation, hepatitis B, C and HIV tests and liver function tests. • The patient should be admitted to hospital and haemoglobin estimation carried, out. Blood is also grouped and cross-matched for use in emergency. 47
  48. 48. • surgery is best earned out on Thursdays and Fridays, since bleeding is most likely on the day of operation or from 4 to 10 days postoperatively. • All surgical procedures must be covered with AHF which is given 1 hour preoperatively. the dose of AHF given before operation depends both on the severity of haemophilia and the amount of trauma expected . Factor VIII is effective only for about 12 hours and therefore must be given regularly at least twice-daily postoperatively for major surgery. Trauma to the head and neck: Haemophiliacs with head and neck injuries are at risk from bleeding into the cranial cavity or into the fascial spaces of the neck. They should, therefore, be given factor replacement to a level of 100 per cent prophylactically after a head or facial trauma. If there are lacerations that need suturing, a minimum level of Factor VIII of 50 percent is required at the time, with further cover for 3 days. Other considerations: Haemophiliacs with inhibitors: • Between 5 and 20 per cent of haemophiliacs who have had multiple infusions, and a few who have not, develop inhibitory antibodies, which reduce the activity of Factor VIII. These problems are most common in severe haemophilia. • Bleeding episodes are not more frequent when inhibitors are present but are more difficult to control. Two types of inhibitor are known high and low litre inhibitors. • In general, those with low titre inhibitors can have dental treatment in the same way as those who have no antibodies. However, in those with high titre inhibitors surgery and other traumatic procedures must be avoided unless absolutely essential. • If the concentration of inhibitors is low Factor VIII may be effective for 4-5 days or longer if immunosuppressive therapy' such as prednisolone or 48
  49. 49. cyclophosphamide is given. In those with higher concentrations of inhibitors, monoclonal antibody-purified Factor VIII infusion or recombinant Factor VIII can often be effective. • Human Factor VIII Inhibitor Bypassing Fractions (FEIBA) are also available; these are usually either non-activated prothrombin complex concentrates (PCC) or activated prothrombin complex concentrates (APCC) which act by activating Factor X directly bypassing the intrinsic pathway of blood clotting. • The danger with these products is of uncontrolled coagulation with thromboses. In many cases, desmopressin is an effective alternative and antifibrinolytics may help, or immunosuppression may be required. Hepatitis, infection with HIV and liver disorders: Haemophilics are at risk from viral hepatitis and infection with HIV. Many patients treated before blood products were screened for hepatitis B or heat-treated against HIV are particularly at risk, Hepatitis C and D infection, however, are increasingly prevalent. Bleeding aggravated by drugs: Aspirin or other non-steroidal anti-inflammatory drugs such as indomethacin should not be given to patients with haemophilia since they can cause gastric bleeding and worsen the haemorrhagic tendency by depressing platelet aggregation. Codeine and paracetamol are safer alternative analgesics. Anxiety: Many haemophiliacs are acutely anxious about dental treatment. Emotional factors significantly increase fibrinolytic activity so that reassurance and use of sedatives may be helpful. Drug dependence: The severe pain from Hemarthrosis may occasionally lead to drug dependence, but this is uncommon. CHRISTMAS DISEASE (HAEMOPHILIA B): 49
  50. 50. Christmas disease (Factor IX deficiency) is clinically identical to haemophilia A and inherited in the same way, but it is about one-tenth as common as haemophilia A. Female carriers often have a bleeding tendency. Dental management of haemophilia B: • The earlier comments on dental management in haemophilia A apply equally to patients with haemophilia B, but Factor IX replacement is needed before surgery and desmopressin is not used. • Human dried Factor IX concentrate is supplied as a powder to be reconstituted with sterile distilled water for intravenous administration. A dose of 20 units Factor IX per kg body weight is used intravenously I hour preoperatively. • The standard preparation may also contain Factors II, VII and X. Factor IX is more stable than Factor VIII. Its half-life is often up to 2 days, so that replacement therapy can sometimes be given at longer intervals than in haemophilia A. VON WILLEBRAND'S DISEASE: • Von Willebrand's disease (pseudohaemophilia) is the most common inherited bleeding disorder and affects about 1 % of the population. It is caused by a deficiency of, or defect in, von Willebrand factor (vWF). • The vWF, synthesized in endothelium and megakaryocytes, normally acts as a carrier for Factor VIII protecting it from proteolytic degradation. • A deficiency in vWF thus leads to a low Factor VIII concentration in the blood. vWF also bridges between platelets and damaged endothelium. Thus the bleeding tendency in von Willebrand's disease results both from a clotting defect and a defect in platelet function. • Von Willebrand's disease not only affects females as well as males but the clinical presentation usually differs from haemophilia A . 50
  51. 51. • The common pattern is bleeding from mucous membranes, with purpura of mucous membranes and the skin. Gingival haemorrhage is more common than in haemophilia. Excessive menstrual bleeding is a common presentation in females. Hemarthrosis are rare • . Although the disorder is usually less severe than haemophilia A, postoperative haemorrhage may be troublesome. • The low level of vWF results in poor platelet adhesion after trauma. Platelets usually fail to aggregate in the presence of ristocetin so that, unlike haemophilia, purpura is common and the bleeding time is prolonged but the best assay is the ristocetin cofactor assay. • Von Willebrand's disease is thus characterized by a prolonged bleeding time, usually a prolonged APTT, low levels of von Willebrand's factor (Factor VIIIR:Ag), and low Factor VIIIC and VIIIR:RCo (ristocetin cofactor) levels. There are various types of von Willebrand's disease and the severity varies from patient to patient and from time to time. Some patients have a clinically insignificant disorder, while others have Factor VIII levels low enough to cause severe clotting defects as well as a prolonged bleeding time. However, the severity does not correlate well with the Factor VIII level. Pregnancy and the contraceptive pill may cause transient amelioration. Von Willebrand's disease has over 20 variants but 80% have type I and nearly 20% have type II disease. It is usually inherited as an autosomal dominant but a severe form of the disease may be inherited as a sex-linked recessive trait like true haemophilia. Rarely, von Willebrand's disease may be acquired, particularly in patients with autoimmune or lymphoproliferative diseases. Dental management in von Willebrand's disease: • Aspirin and NSAIDs should be avoided. In most patients with von Willebrand's disease, the haemostatic defect can be controlled with desmopressin, now mainly given via a nasal spray. The chief exceptions are, first, type IIB disease, in which desmopressin is contraindicated because it stimulates release of dysfunctional von Willebrand factor which leads, in turn, to platelet aggregation and severe but transient thrombocytopenia. Second, it is also contraindicated in type III .disease, 51
  52. 52. where so little von Willebrand factor is formed that essentially the same management is required as for haemophilia A. However, since Factor VIII has a prolonged half-life, less frequent infusions may be required. Thus type I von Willebrand's disease can be treated with desmopressin but types II and III require clotting factor replacement. Hereditary haemorrhagic telangiectasia, mitral valve prolapse, or Factor XII deficiency may be associated and may require to be considered in the management plan. OTHER CONGENITAL COAGULATION DEFECTS: • Factor XI deficiency (plasma thromboplastin antecedent deficiency) is one of the more common other congenital coagulation defects and is sometimes known as haemophilia C. • Any of the other clotting factors can be deficient and all may be associated with a haemorrhagic tendency, except Factor XII deficiency (despite the prolonged clotting time and APTT in this defect there is actually a tendency to thromboses). • Most are uncommon or rare defects. Fresh frozen plasma will usually correct most of these coagulation defects, but local haemostatic measures should also be applied. ACQUIRED COAGULATION DEFECTS: Acquired haemorrhagic disorders are much more prevalent than the congenital diseases but, except in anticoagulant therapy or liver disease, are usually less severe. Important causes include: 1. Anticoagulant therapy. 2. Vitamin K deficiency or malabsorption. , 3. Liver disease (deficiency of Factor XII). 4. Disseminated intravascular coagulation. 5. Fibrinolytic states. 6. Amyloidosis (deficiency of Factor X). 7. Autoimmune disorders (deficiency of Factor VIII) Nevertheless, some of those with clinical bleeding tendencies do not have a defect detectable by current laboratory methods. 52
  53. 53. Anticoagulant treatment: • The commonly used anticoagulants are coumarins, such as warfarin, for long-term, and heparin for short-term treatment. • Anticoagulants are given for thromboembolic disease but their use varies widely (Table). Anticoagulants result in a bleeding tendency but, generally, postoperative haemorrhage will eventually subside spontaneously. Nevertheless, severe blood loss can occur. • Coumarins such as warfarin are given orally and antagonize the action of vitamin K so that the prothrombin and activated partial thromboplastin times are prolonged. The effects are delayed for 8-12 hours, are maximal at 36 hours, but persist for 72 hours. • Nicoumalone and phenindione are seldom used. Oral anticoagulants are teratogenic. Coumarin anticoagulant therapy should maintain a prothrombin time of 2-2 1/2 times the control (control 11-15 seconds), or a thrombotest of 5-20 per cent. Important Conditions for which Anticoagulants may be used: * Atrial fibrillation . * Cerebral Thrombosis * Deep vein thrombosis * Embolization secondary to myocardial infarction * Heart valve replacements *Renal dialysis. • prothrombin times are often now recorded as the international normalized ratio (INR), a ratio of 2-3 being the usual therapeutic range for deep vein thrombosis, and up to 4.5 being required for patients with prosthetic heart valves. . • Heparin is not given orally but by injection and acts immediately, mainly by inhibiting the thrombin-fibrinogen reaction. The prothrombin, activated partial thromboplastin {APTT) and thrombin times are therefore prolonged. Most patients are monitored with the APTT. Platelet counts should also be monitored if heparin is used for more than 5 days, since thrombocytopenia 53
  54. 54. can result. The anticoagulant effect of heparin is usually lost within less than 6 hours of stopping heparin. Low molecular weight heparins, which include dalteparin, enoxaparin and tinzaparin, have a longer duration of action. Related agents include danaparoid, ancrod and epoprostenol. There should be no interference with anticoagulant treatment without the agreement of the clinician in charge. Neglect of this important point has led to rebound thrombosis which has damaged prosthetic cardiac valves and even caused thrombotic deaths. Dental management of patients on oral (coumarin) anticoagulation: • The prothrombin time (PT) is the standard laboratory test for monitoring oral anticoagulant activity. • Blood (citrated) for the prothrombin time is tested as soon as possible (within a few hours of venepuncture) by adding calcium and tissue thromboplastin to activate the clotting cascade (Table). • The prothrombin rime is expressed as the ratio of the PT of the patient (in seconds) to that of a control value but because the thromboplastin and the control values vary between laboratories, leading to different meanings of PT, an INR has been devised, this being the PT ratio (patient's PT/control PT) that would have been obtained if an international reference thromboplastin type 67/40 had been used, In a person with a PT within the normal range, the INR is approximately 1. It is important to recognize that the INR is valid only for patients on stable anticoagulant therapy. • Patients on coumarin anticoagulants should not have their medication stopped or changed before dental treatment except under special supervision. Minor surgery (simple extractions of two or three teeth) may be carried out safely with no change in anticoagulant treatment if the prothrombin rime is within 1.5-3 times normal (INR up to 3.5). Regional blocks should be avoided. Surgery should be as atraumatic as possible, and a little haemostatic material (e.g. oxidized cellulose or fibrin), but is not essential. • Patients requiring major oral surgery are best admitted to hospital 48 hours before the operation, as are patients with INR above 3.5 and, with the agreement of the 54
  55. 55. clinician in charge, anticoagulation may need to be modified. If anticoagulants are to be continued, vitamin K should preferably be avoided as it makes subsequent anticoagulation difficult. • If postoperative bleeding occurs, vitamin K may be given to counteract the coumarins. If the use of vitamin K cannot be avoided, only 10 mg should be given. In an emergency an antifibrinolytic agent (tranexamic acid) can be used to control haemorrhage. Patients on oral anticoagulants are especially at risk from haemorrhage under the following circumstances. 1. Irregular tablet taking. 2. Liver disease or obstructive jaundice, which impairs vitamin K metabolism or absorption. 3. Prolonged antimicrobial therapy (azole antifungals, penicillins, metronidazole, erythromycin, cephalosporins). 4. Liquid paraffin which leads to loss of vitamin K (theoretically). 5. Use of protein-binding drugs which displace the anticoagulant from plasma proteins and enhance its effect, e.g. aspirin, azole antifungals and sulphonamides. Co-trimoxazole, which contains a sulphonamide, and azoles, even as oral gels, may therefore be contraindicated. 6. Use of aspirin and other non-steroidal anti-inflammatory agents which can cause gastric bleeding and also interfere with platelet function. 7. Withdrawal of barbiturates; this decreases the breakdown of anticoagulants. Under such circumstances the thrombotest should be repeated within 24 hours of surgery. Dental management of patients on heparin anticoagulation: o The effect of heparin is best assessed by the thrombin time, which is usually maintained at 3-4 times normal (control 10-12 seconds). Low dose heparin therapy such as 'Minihep' (used to reduce postoperative complication of deep vein thrombosis) may have little effect on the thrombin time, APTT or on postoperative bleeding. o Heparin is given intravenously and its use is therefore restricted to inpatients. It has an immediate effect on blood clotting but acts for only 4-6 hrs, so that no specific treatment is needed to reverse its effect. This can be achieved immediately during 55
  56. 56. an emergency by intravenous protamine sulphate given in a dose of 1 mg per 100 IU heparin. Usually there is no need to interfere with anticoagulant treatment for simple extractions. o Surgery can safely be carried out after 6-8 hours, when the effects of heparinization have ceased. Low molecular weight heparins act for up to 24 hours, however. In renal dialysis patients surgery is best carried out on the day after dialysis as the effects of heparinization have then ceased and there is maximum benefit from dialysis. It should be remembered that the condition for which anticoagulant therapy is being given, especially prosthetic heart valves, may also affect dental management. Vitamin K deficiency and malabsorption: o Vitamin K is taken in with the diet and also synthesized by the gut flora. It is a fat- soluble vitamin and its absorption in the small gut depends on the presence of bile salts. After transport to the liver, vitamin K is used for the synthesis of Factors II (prothrombin), VII, IX and X. o Haemorrhagic disease may, therefore, result from too little vitamin K reaching the liver, particularly as a result of obstructive jaundice or malabsorption. Alternatively, vitamin K metabolism may be impaired by anticoagulants or severe liver disease. In the last, many haemostatic functions are severely-impaired and vitamin K is of little or no value. Dental aspects of vitamin K deficiency: Dental management in vitamin K deficiency may be complicated by (a) the clotting defect and (b) the underlying disorder, particularly obstructive jaundice. o The latter may be caused by gallstones, viral hepatitis or carcinoma of the head of the pancreas. o The underlying disorder should preferably be corrected, but vitamin K can be given if surgery is urgent. Phytomenadione (5-25 tng) is the most potent and rapidly acting form and should preferably be given intravenously to avoid intramuscular injection. o The prothrombin time should be monitored after 48 hours, and, if the defect has not been corrected by then, this suggests parenchyma) liver disease. 56
  57. 57. Clotting Defects involving Vitamin K: *Lack of vitamin synthesis in gut: Broad spectrum antibiotics used for prolonged periods or inpatients on Parenteral feeding. *Poor Absorption Malabsorption Syndromes Obstructive Jaundice * Failure of utilization Oral anticoagulant treatment Liver failure Liver disease:  Liver disease is an important cause of bleeding disorders.  The haemostatic defects in liver failure include (a) impaired vitamin K metabolism; (b) increased fibrinolysis; (c) failure of synthesis or increased consumption of normal clotting factors; (d) synthesis of abnormal clotting factors; and (e) thrombocytopenia.  Haemorrhage can be severe and difficult to manage because of the complexity of these defects. Antitibrinolytic treatment and fresh frozen plasma may sometimes be effective. If there is an obstructive element to the disease vitamin K. may be effective, but only if parenchyma] disease is mild. Fibrinolytic drugs and states: Fibrinolytics, such as streptokinase, alteplase, anistreplase and urokinase, and local activation of plasmin by infection for example, may cause abnormal bleeding. Dental surgery should be deferred where possible in patients on fibrinolytic therapy. Acquired haemophilia: This rare disorder is due to circulating antibodies to Factor VIII which typically are of idiopathic origin but may rarely form in rheumatoid arthritis, other autoimmune disorders, and drug therapy especially with penicillin, pregnancy or the puerperium. Specialist haematological attention is required before any invasive dental treatment is considered. 57
  58. 58. Other disorders associated with bleeding tendencies: These include the following: 1. Polycythaemia vera. ,' 2. Myelofibrosis, leukaemia or lymphoma. 3. Chronic renal failure. 4. Cyanotic congenital heart disease. 5. Gram-negative shock. 6. After massive transfusions. 7. Antibodies to clotting factors .8. Head injuries. 58

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