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 o ygen ! nutrients to the tissues and is vital for body functions. "oss of blood due to any reason beyond a certain point is potentially life threatening ! may lead to e sanguinations.

History
#ethod for controlling hemorrhage Ambroise pare$s (%&%'(%&)') position in the evolution of surgery remains of supreme importance. *rom %&+, until -ust before his death. pare was either engaged as an army surgeon. or performing surgery in civilian practice in /aris. 0ther surgeons were using boiling oil as a means of cauteri1ing fresh gunshot wounds. /are$s employment of a less irritating emollient of egg yol2. rose oil ! turpentine brought him lasting fame ! glory. Among /are$s important corollary observations was that in performing an amputation. it was more efficacious to ligate individual blood vessels than to attempt to control hemorrhage by means of mass ligation of tissue or with hot oleum. /are humbly attributed his success to patient$s god as noted in his famous motto. 34e le pansay. 5ien le guerit.6 that is 37 treated him .god cured him.6

Types of hemorrhage
7. 1) External hemorrhage( is one that is revealed outside or seen e ternally. 2)Internal hemorrhage( is one that is not seen from outside. o Also called as concealed hemorrhage e.g.8( Bleeding peptic ulcer ruptured ectopic gestation. fracture of ma-or bones. rupture of liver. spleen etc. 9ometimes concealed hemorrhage may be e ternal hemorrhage. e.g.8( Haematemesis or malaena from bleeding peptic ulcer. haematuria from ruptured 2idney. II Acc. to the source of hemorrhage 1) Arterial hemorrhage( is one which comes from a ruptured artery (7t is bright red color ! is pulsative. 2) Venous hemorrhage( is one which comes from a vein. :haracteri1ed by dar2 red color ! flows out steadily instead of spurts ;ery difficult to stop venous hemorrhage 5ue to lac2 of valves in veins of the facial region ! e tensive 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 ! oo1es rather than flows out ! no bleeding point can be made out.

<

 Bleeding is not severe ! is easily controlled by simple pressure with gau1e pads. 7n coagulation disorders. there can be e tensive blood less from capillaries. . III. According to the time of appearance %) rimary hemorrhage( is one which occurs at the time of in-ury or operation. Hemostatic mechanisms in the body attempt to stop the bleeding by formation of clot <) !eactionary hemorrhage( is one which occurs within <= hours of in-ury or operation. 7n ma-ority of cases it occurs within =(, hours. 0ccurs due to dislodgement of blood clots or slipping of ligatures #ostly occurs due to rise of blood pressure when the patient recovering from anesthesia or shoc2 ! also occurs due to restlessness. coughing or vomiting which raises the venous pressure +) "econdary hemorrhage( is one which occurs after <= hours to >(%= days of in-ury or operation. This is usually due to infection. =) "pontaneous #leeding$ occurs without any provocation. ?.g.8( 7n ac@uired (patients on oral hypoglycaemic agents( decreases platelet count) ! hereditary coagulopathies.

:auses of hemorrhage
%) Trauma to the vessel wall e.g.8( penetrating wound in the heart or great vessels. during labour etc. +

<) 9pontaneous hemorrhage e.g.8( rupture of an aneurysm. septicaemia. bleeding deathesis. acute leu2emia. pernicious anemia. scurvy. +) 7nflammatory lesions of the vessel wall e.g.8( bleeding from chronic peptic ulcer. typhoid ulcer. blood vessels transversing a tuberculous cavity in the lung. syphilitic involvement of the aorta. poly arthritis nodosa. =) Aeoplastic invasion e.g.8( hemorrhage following vascular invasion in carcinoma of tongue. &) ;ascular diseases( e.g.8( atherosclerosis. ,) ?levated pressure within the vessels e.g.8( cerebral ! retinal hemorrhage in systemic hypertension.

?ffects of hemorrhage
The effects of blood loss depend upon + main factors %) The amount of blood loss <) The speed of blood loss +) The site of hemorrhage The loss up to <'B of blood volume suddenly or slowly generally has little clinical effects because of compensatory mechanisms. A sudden loss of ++B of blood volume may cause death. while loss of up to &'B of blood volume over a period of <= hours may not be necessarily fatal. :hronic blood loss generally produces an iron deficiency anemia. where as acute hemorrhage may lead to serious immediate conse@uences such as hypovolemic shoc2.

:linical features of hemorrhage

7ncreased pulse rate. low blood pressure. increasing pallor. restlessness and deep signing respiration ( air hunger) are the typic features of acute blood loss. :old ! clammy e tremities. empty veins are also characteristically seen which the bleeding is continuing. /ulse rate ! blood pressure should be measured C or D hourly intervals when the patient is losing blood. Though fall of B./ is often noticed in case of hemorrhage. yet a normal B./ cannot e clude the diagnosis of hemorrhage. 0ften the B./ is maintained at normal level by peripheral vasoconstriction due to adlenergic release when the patient is still bleeding. 9uddenly the B./ 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 e cessive the pulse becomes of low volume. which is classically 2nown as thready pulse. #easuring of urine output is obligatory in patient who is losing blood. Erine output becomes low in patients suffering from hemorrhage ! shoc2.

#easurement of blood loss

7t 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 s2in. This loss of plasma ! water constitutes &

appro imately <'B 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) %eighing of s&a# The swabs are weighed before they are used ! they are weighed again after they are soa2ed with blood ! thrown individually into a collecting bas2et. The difference of weight is the amount of blood loss. %gmF%ml of blood loss 7t cannot give the actual amount of blood loss ! it should be multiplied by a factor of % D in case of moderate operations. 7n case of longer operations the swab weighing total should be multiplied by a factor of <. 2) 'easurement of s&elling in closed fractures 7n case of moderate swelling in closed fractures of the tibia. the blood loss is estimated at %''' to %&'' ml. 7n moderate swelling in case of fractured shaft of femur. the estimated blood loss is about %''' to <''' ml. 3) 'easurement of #lood clot Ghen the collected blood clots are 2ept in a pot ! measured against a clenched fist of the patient. total blood clot of the si1e of the clenched fist is e@ual to &''ml of blood.

Blood volume determinations

Blood volume F red cell volume + plasma volume. Haematoceit reading gives the ratio of plasma to red cells. *irstly the plasma volume or the red cells volume is measured ! from the haematocrit valve the total blood volume can be ,

determined the normal blood volume is about H' ml of whole blood per 2g body weight that means in case of an adult of normal structure the normal blood volume is about & to , liters. 7n certain pathological conditions this blood volume is increased e.g.8(chronic anemia ! arterio(venous fistula. Hemoglobin level8 practically not so. 7n the initial stage the hemoglobin level remains normal. 7t is only lowered after a few hours by haemodilution caused by movement of e tra cellular fluid into the vascular space due to nature attempt to restore blood volume. #easurement of :;/8 ( Iood method to detect loss of blood volume in hemorrhage.

( 7t is often considered as a good indication of hemorrhage.

But it is

H?#09TA979 ! B"005 :0AIE"AT07A

The term hemostasis means prevention of blood loss. whenever a vessel is severed or ruptured.hemostasis is achieved by several mechanismsJ %. ;ascular spasm. <. *ormation of platelet plug. +. *ormation of a blood clot as a result of blood coagulation. =. ?ventual growth of fibrous tissue into the blood clot to close the hole in the vessel permanently. Vascular constriction K 7mmediately after a blood vessel has been cut or ruptured. the trauma to the vessel wall itself causes the vessel to contractJ this instantaneously reduces the flow of blood from the vessel rupture.

>

K The contraction results from nerve refle es. local myogenic spasm. local humoral factors from the traumati1ed tissues !blood platelets. K *or the smaller vessels platelets are responsible for much of the vasoconstriction by releasing the vasoconstrictor substance thrombo ane A<. K The local vascular spasm can last for many minutes or even hours. during which time the processes of platelet plugging ! blood coagulation can ta2e place.

(ormation of the platelet plug 7f the vent is very small( ! many very small vascular holes do develop throughout the body each day Lit is often sealed by a platelet plug rather than by a blood clot. Characteristics of platelets /latelets in their cytoplasm contain active factors such as (%) 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. (<) Residuals of both the endoplasmic reticulum and the golgi apparatus that synthesi1e various en1ymes and especially store large @uantities of calcium ions. (+)#itochondria and en1yme systems that are capable of forming adenosine triphospahte and adenosine diphosphate (A5/). (=) ?n1yme systems that synthesi1e prostaglandins. which are local hormones that cause many types of vascular and other local tissue reactions. (&)An important protein called fibrin(stabili1ing factor (,) 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. H

K The cell membrane of the platelet is also important. 0n 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 in-ured areas of the vessel wall K :ontains large amounts of phospholipids that play several activating roles at multiple points in the blood clotting process.

'echanism of platelet plug Ghen 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 stic2y so that they adhere to collagen in the tissue and a protein called von willebrand factor that spreads throughout the plasmaJ They secrete large @uantities of A5/ and their en1ymes form thrombo ane A<. the A5/ and thrombo ane inturn act on nearby platelets to activate them as well and the stic2iness 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 e tra vascular tissue elicit activation of successively increasing numbers of platelets

that themselves attract more and more additional platelets. thus forming a platelet plug.

)lood coagulation in the ruptured *essel

The third mechanism for hemostasis is formation of the blood clot. The clot begin to develop in %& to <' seconds if the trauma to the vascular wall has been severe and in % to < minutes if the trauma has been minor. Activator substances from the traumati1ed vascular wall. from platelets. and from blood proteins adhering to the traumati1ed vascular wall initiate the clotting process. Githin + to , minutes after rupture of a vessel. if the vessel opening is not too large the entire opening bro2en end of the vessel is filled with clot. After minutes to an

%'

hour. the clot retractsJ this closes the vessel still further.

%%

fi#rous organi+ation or ,issolution of the #lood clot

K 0nce a blood clot has formed. it can follow one of two courses (%) it can become invaded by fibroblasts. which subse@uently form connective tissue all through the clot. or (<) 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 organi1ation of the clot into fibrous tissue within about % to < wee2s. 'echanism of #lood coagulation )asic theory KK #ore than &' 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. KK Ghether blood will coagulate depends on the balance bMw these < groups of substances. KK 7n 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. -eneral mechanism All research wor2ers in the field of blood coagulation agree that clotting ta2es place in + essential steps. %) 7n response to rupture of the vessel or damage to the blood itself. a comple cascade of chemical reaction occurs in the blood involving more than a do1en %<

coagulation factors the net result is formation of a comple of activated substances collectively called prothrombin activator. <) The prothrombin activator cataly1es the conversion of prothrombin into thrombin. +) =) The thrombin acts as an en1yme to convert fibrinogen into fibrin fibers that enmesh platelets. blood cells ! plasma to form the clot. Con*ersion of prothrom#in into throm#in KK 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. KK The thrombin in turn causes polymeri1ation of fibrinogen molecules into fibrin fibers within another %' to %& seconds. KK /latelets 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

%+

damaged tissue. Then this binding accelerates the formation of still more thrombin from

rothrom#in . /hrom#in %=

KK /rothrombin is formed continually in the liver and it is continually being used throughout the body for blood clotting. 7f 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. KK ;itamin N is re@uired by the liver for the normal formation of prothrombin as well as for formation of = other clotting factors. Therefore either lac2 of vitamin N or the presence of liver disease that prevents normal prothrombin formation can decrease the prothrombin level so low that a bleeding tendency results.

Con*ersion of fi#rinogen into fi#rin$ formation of the clot

Fibrinogen8 Because of their large molecular si1e. little fibrinogen normally lea2s 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. Ghen the permeability of the capillaries become pathologically increased. fibrinogen does lea2 into the tissue fluids in sufficient @uantity to allow clotting of these fluids in much the same way that plasma and whole blood clot. Action of throm#in on fi#rinogen to form fi#rin K Thrombin is a protein en1yme with wea2 proteolytic capabilities. K 7t 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 polymeri1e with other fibrin monomer molecules. thus forming fibrin. K Therefore many fibrin monomer molecules polymeri1e within seconds into long fibrin fibers that then constitutes the reticulum of the clot. %&

K 7n the early stages of this polymeri1ation. the fibrin monomer molecules are held together by wea2 noncovalent hydrogen bonding. and the newly forming fibers are not cross lin2ed with one another therefore the resultant clot is wea2 and can be bro2en apart with ease. K But then. another process occurs during the ne t few minutes that greatly strengthen the fibrin reticulum. This involves a substance called fibrin stabili1ing factor that is normally present in small amounts in the plasma globulins but is also released from platelets entrapped in the clot. K Before fibrin stabili1ing 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 stabili1ing factor. K Then this activated substance operates as an en1yme to cause covalent bonds bMw more !more of the fibrin monomer molecules. as well as multiple cross(lin2ages bMw ad-acent fibrin fibres.thus adding tremendously to the + dimensional strength of the fibrin meshwor2. /he #lood clot The clot is composed of a meshwor2 of fibrin fibres running in all directions ! entrapping blood cells.platelets.!plasma.. The fibrin fibers also adhere to damaged surfaces of blood vesselsJ therefore the clot becomes adherent to any vascular opening !thereby prevents further blood loss. Clot retraction$serum Githin a few minutes after a clot is formed. it begins to contract and usually e presses most of the fluid from the clot within <' to ,' minutes.

%,

The fluid e pressed is called serum because all its fibrinogen and most of the other clotting factors have been removed in this way. serum differs from plasma. 9erum cannot clot because it lac2s these factors.

K /latelets 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. K /latelets entrapped in the clot continue to release procoagulant substances. one of which is fibrin stabili1ing factor. which carses more and more cross lin2ing bonds bMw the ad-acent fibrin fibers. 7n 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 meshwor2 into a smaller mass. K 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. K As the clot retracts. the edges of the bro2en blood vessel are pulled together thus contributing still further to the ultimate state of homeostasis.

Initiation of coagulation0 (ormation of prothrom#in acti*ator

/rothrombin activator is generally considered to be formed in two ways. although. in reality the two ways interact constantly with each other8 (%) by the e trinsic pathway that begins with trauma to the vascular wall and surrounding tissues and (<) by the intrinsic pathway that begins in the blood itself. 7n both the e trinsic and the intrinsic pathway. a series of different plasma proteins called blood(clotting factors play ma-or roles. %>

#ost of these are inactive forms of proteolytic ec1ymes. Ghen converted to the active forms. their en1ymatic actions cause the successive. cascading reactions of the clotting process.

Extrinsic path&ay for initiating clotting

The e trinsic pathway for initiating the formation of prothrombin activator begins with a traumati1ed vascular wall or e tra vascular tissues that come in contact with the blood. %) Release of tissue factor. Traumati1ed tissue releases a comple of several factors called tissue factor or tissue thromboplastin. This is composed especially of phospholipids from the membranes of the tissues plus a lipoprotein comple that functions mainly as a proteolysis en1yme. <) Activation of factor O( role of factor ;77 and tissue factor. The lipoprotein comple of tissue factor further comple es with blood coagulation factor ;77 and in the presence of calcium ions. acts en1ymatecally on factor O to form activated factor O (Oa). +) ?ffect of activated factor O (Oa) to form prothrombin activator( role of factor ;. the activated factor O combines immediately with tissue phospholipids that are part of tissue factor or with additional phospholipids released from platelets as well as with factor ; to form the comple called prothrombin activator. Githin afew seconds. in the presence of calcium ions (:a++). this splits prothrombin to form thrombin. and the clotting process proceeds as already e plained. At first. the factor ; in the prothrombin activator comple is inactive. but once clotting begins and thrombin activates factor ;. this then becomes an additional strong accelerator of prothrombin activation. Thus in the final prothrombin activator comple . activated %H

factor O is the form thrombin activated factor ; greatly accelerates this protease activity. and platelet phospholipids act as a vehicle that further accelerates the process. Aote especially the positive feedbac2 effect of thrombin acting through factor ;. in accelerating the entire process once it begins.

Intrinsic path&ay 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 e posure of the blood to collagen from a traumati1ed blood vessel of the blood to collagen from a traumati1ed blood vessel wall. %) Blood trauma causes (%) activation of factor O77 and (<) release of platelet phospholipids. Trauma to the blood or e posure of the blood to vascular wall collagen alters two important clotting factors in the blood8 factor O77 and the platelets. Ghen factor O77 is disturbed. such as by coming into contact with collagen or with a wettable surface such as glass. it ta2es on a new molecular configuration that converts it into a proteolytic en1yme called 3activated factor O776. 9imultaneously. 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 +. which also plays a role in subse@uent clotting reactions. <) Activation of factor O7. The activated factor O77 acts en1ymatically on factor O7 to activate this factor as well. which is the second step in the intrinsic pathway. This reaction also re@uires H#G (high molecular weight) 2ininogen and is accelerated by pre2alli2rein. %)

+) Activation of factor 7O by activated factor O7. The activated factor O7 then acts en1ymatic ally on factor 7O to activate this factor also. =) Activation of factor O( role of factor ;777. The activated factor 7O. acting in concert with activated factor ;777 and with the platelet phospholipids and factor + from the traumati1ed platelets. activates factor O. 7t is clear that when either factor ;777 or platelets are in short supply. this step is deficient. *actor ;777 is the factor that is missing in a person who has classic hemophilia. for which reason it is called antihemophilic factor. /latelets are the clotting factor that is lac2ing in the bleeding disease called thrombocytopenia. &) Action of activated factor O to form prothrombin activator( role of factor ;. This step in the intrinsic pathway is the same as the last step in the e trinsic pathway. That is activated factor O combines with factor ; and platelet or tissue phospholipids to form the comple 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.

!ole of calcium ions in the intrinsic and extrinsic path&ays

? cept for the first two steps in the intrinsic pathway. calcium ions are re@uired 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 #1& the extrinsic . intrinsic path&ays$ summary of #lood clotting initiation
7t is clear from the schemas of the intrinsic ! e trinsic systems that after blood vessels rupture. clotting occurs by both pathways simultaneously. Tissue factor initiates the <'

e trinsic pathway whereas contact of factor O77 and platelets with collagen in the vascular wall initiates the intrinsic pathway. An especially important difference bMw the e trinsic and intrinsic pathways is that the e trinsic pathway can be e plosiveJ once initiated its speed of occurrence is limited only by the amount of tissue factor released from the traumati1ed tissues and by the @uantities of factors O. ;77. and ; in the blood. Gith severe tissue trauma. clotting can occur in as little as %& seconds. The intrinsic pathway is much slower to proceed. usually re@uiring % to , minutes to cause clotting.

re*ention of #lood clotting in the normal *ascular system$ the intra*ascular anticoagulants
?ndothelial surface factors /robably the most important factors for preventing clotting in the normal vascular system are (%) the smoothness of the endothelial surface. which prevents contact activation of the intrinsic clotting systemJ (<) a layer of glycocaly on the endothelium (glycocaly is a mucopolysaccharide adsorbed to the surface of the endothelium). which repels clotting factors and platelets. thereby preventing activation of clottingJ and (+) a protein bound with the endothelial membrane. thrombomodulin. which binds thrombin. Aot only does the binding of thrombomodulin with thrombin slow the clotting process by removing thrombin. but the thrombomodulin thrombin comple also activates a plasma protein. protein :. that acts as an anticoagulant by inactivating activated factors ; and ;777.

<%

K Ghen the endothelial wall is damaged its smoothness and its glycocaly thrombomodulin layer are lost. which activates both factor O77 and the platelets. thus setting off the intrinsic pathway of clotting K 7f factor O77 and platelets come in contact with the subendothelial collagen. the activation is even more powerful.

A2/I/H!3')I2 AC/I32 3( (I)!I2 .A2/I/H!3')I2 III Among the most important anticoagulants in the blood itself are those that remove thrombin from the blood. the most powerful of these are %. the fibrin fibers that themselves are formed during the process of clotting ! <. an alpha(globulin called antithrombin 777 or antithrombin(heparin cofactor. K Ghile a clot is forming. about H&()' percent of the thrombin formed from the prothrombin becomes adsorbed to the fibrin fibers as they develop. K This helps prevent the spread thrombin into the remaining blood !therefore. prevents e cessive spread of clot. K The thrombin that does not adsorb to the fibrin fibers soon combines with antithrombin 777.which further bloc2s the effect of the thrombin on the fibrinogen !then also inactivates the thrombin during the ne t %<(<' min. HE A!I2 K 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.

<<

K By itself. it has little or no anticoagulant property. but when it combineswith antithrombin 777. the effectiveness of antithrombin 777 in removing thrombin increases by a hundredfold to a thousandfold and thus it acts as an anticoagulant. K Therefore. in the presence of e cess heparin. the removal of free thrombin from the circulating blood by antithrombin 777 is almost instantaneous. K The comple of heparin and antithrombin 777 removes several other activated coagulation factors in addition to thrombin. further enhancing the effectiveness of anticoagulation. The other includes activated factors O77. O7. 7O and O. K Heparin is produced by mast cells ! basophiles.

4ysis of #lood clots$plasmin

The plasma proteins contain a euglobulin called plasminogen (or profibrinolysin) that when activated. becomes a substance called plasmin (or fibrinolysin). /lasmin is a proteolytic digestive en1yme of pancreatic secretion. /lasmin digests fibrin fibers as well as other protein coagulants such as fibrinogen. factor ;. factor ;777. prothrombin and factor O77. 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.

Acti*ation of plasminogen to form plasmin0 then lysis of clots.

Ghen 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 in-ured tissues and vascular endothelium very slowly release a powerful activator called tissue plasminogen activator (t((/A) that a day or so later. after the <+

clot has stopped the bleeding eventually converts plasminogen to plasmin. which in turn removes the remaining blood clot. 7n fact many small blood vessels in which the blood flow has been bloc2ed 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 e*aluation of the #leeding patient HI"/3!5

a) Any personal or family history of a bleeding tendency b) Bleeding problems after surgery or dental e traction. c) Bleeding problems after trauma d) #edication that cause bleeding (Aspirin.anticoagulants.long term antibiotic therapy e) /resence of illness that may have associated bleeding problems(leu2emia.liver disease.hemophilia.congenital heart disease.renal disease f) 9pontaneous bleeding from nose.ears.mouth.and so on.

/hysical e amination
:hec2 for adenopathy. splenomegaly or hepatomegaly Assessment of the s2in ! mucosal surface

<=

 Bleeding into superficial s2in ! soft tissues usually such as small capillary hemorrhage ranging from petechia to ecchymoses characteristic of abnormalities of the vessels or platelets Hemorrhage into synovial -oints is diagnostic of a severe coagulation disorder.

"aboratory tests for screening

#a-ority of defects of hemostasis can be screened by = basic tests.

%. Bleeding time8
9ensitive measure of platelet function Aormal bleeding time is less than %' minutes /rolonged in thrombocytopenia. von wille brand$s disease ! platelet dysfunction

<. /latelet count

Aormal platelet count is %.&'.''' to =.&'.''' per ml of blood Ghen count becomes &'.''' to %.''.''' per ml. there is mild prolongation of bleeding time. so that bleeding occurs after severe trauma or surgery. P &'''' per ml results in easy bruising manifests as petechia ! ecchymoses during trauma or surgery. P <'.''' per ml L spontaneous bleeding may be intracranial or any other internal bleeding. #inor oral surgical procedure can be safely done. if platelet count is above H'.''' to %.''.''' per ml. otherwise platelet needs transfusion of platelet rich plasma. <&

+. /rothrombin time (/T)

9creens the e trinsic limb of coagulation pathway factor ;. ;77.O ! factor 7. 77 ! ; of the common pathway Aormal /T is %<(%= second /rolonged in patients on warfarin anticoagulant therapy. vitamin N deficiency of factor ;. ;77. O. prothrombin ! fibrinogen As a general guideline for dental procedures. the /T should be less than % D of the control value.

=. /artial thromboplastin time (/TT) 9creens the intrinsic limb of coagulation pathway ! tests for the ade@uacy of factor 7. 77. ; of the common pathway /TT is prolonged in haemophilic patients. Aormal /TT is P =& seconds. 7f both /T ! /TT are of prolonged. then factor 77. ;. O or vitamin N deficiency ! liver disease are suspected.

Management of hemorrhage
9urgical bleeding. even when alarmingly e cessive. 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.

<,

This may be accomplished by interrupting the flow of blood to the involved area or by direct closure of the blood vessel wall defect . Rest8 ( Absolute rest is vital as far as the treatment of hemorrhage is concerned. Restlessness causes more bleeding. 9ome sedatives ! analgesics may be prescribed to provide rest to the patient. #orphine is a good sedative ! given <& mg 7;M7#. #orphine is contraindicated when there is respiratory depression in head in-uries. in children ! in very old individuals where chloral hydrate is preffered. 9edative may be prescribed along with morphine. 9hort acting tema1epam ! ben1odia1epam may sense.

The techniques may be classified as mechanical, thermal or chemical.

%) 'echanical procedure
1) ressure The oldest mechanical device to effect closure of the bleeding point is by pressure application. Ghen pressure is applied to an artery pro imal to an area of bleeding. profuse bleeding is reduced. permitting more definitive action. <>

 /ressure should be applied directly over the bleeding site for at least & minutes. The obvious disadvantage of digital pressure is that it cannot be used for a long period. 7n case of oo1ing from bone. bone wa may be used. <) Hemostat0 ( (artery forceps) The hemostat also represents a temporary mechanical device to stem bleeding. 7n smaller ! non critical vessels. the trauma ! ad-acent tissue necrosis associated with the application of a hemostat are of little conse@uence. These minor disadvantages are weighed by the mechanical advantage that the instrument offers to subse@uent ligation.

3) 4igature Replaces the hemostat as a permanent method of effecting hemostasis in a single vessel Ghen a large vessel has to be tied +(' non absorbable material is preferred. 9maller vessels can be ligated with +(' catgut or polygalactin. *or large arteries with pulsation and longitudinal motion. transfi ion suture to prevent slipping is indicated. The T. adventitia ! T. media constitute the ma-or holding forces within the walls of large vessels and therefore multiple fine sutures as preferable to fewer larger sutures. 6) Em#oli+ation of the *essels <H

 ;essels that are usually investigated for treatment of oral ! perioral lesions include the facial. lingual. transverse facial ! internal ma illary arteries. After the individual vessels are identified. contrast media is in-ected via the lesions are completely mapped angio graphically. emobli1ation of bleeding vessel can be carried out. Agents used for emboli1ation are steel coils. polyvinyl alcohol foam. gel foam. silicon spheres ! methyl methacrylate. <) Thermal agents I. Cautery Heat achieves hemostasis by denaturation of proteins which results in coagulation of large areas of tissue. 7n cauteri1ation. heat is transmitted from the instrument by conduction directly to the tissues. ?ven dental burnisher li2e instrument can be directly heated over a flame ! applied directly to the bleeding point in the oral cavity. II. Electrosurgery 7n electro surgery. heating occurs by induction from an alternating current source. Advantage8 ( saves time. 5isadvantages8 ( burning smell ! smo2e during application. :annot control hemorrhage from the large vessels. :ertain anesthetic agents cannot be used with electrocautery because of the ha1ard of e plosion. III. Cooling <)

 5irect cooling with iced saline is effective ! acts by increasing the local intra vascular hematocrit ! decreasing blood flow by vasoconstriction. ? treme cooling that is cryogenic surgery has been applicable particularly in gynecology ! neurosurgery. Temperatures ranging between (<' to (%H': are used and at temp (<': or below. the tissue capillaries. small arterioles and venules undergo cryogenic necrosis. IV. Argon$#eam coagular Aew form of electro cautery ! more effective than electrocautery 7n this. coagulator monopolar current is transmitted to tissues through the flow of argon gas. This allows bleeding from vessels that are smaller than +mm in diameter to be controlled without the use of hemostat or ligatures. The tip of the coagulator is held appro imately app.%cm from tissue. A flow of argon gas clears the surgical site of fluids to allow current to be focused directly on tissue. with reduced carboni1ation. There is formation of % to <mm of ?scher 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 ris2 can be eliminated by not placing hand piece tip in direct contact with tissues. V. 4asers Results in bloodless surgery as there effectively coagulate the small blood vessels during cutting of tissues. +'

3) Chemical agents(
4ocal agents

local ! systemic

:hemical agents vary in their hemostatic action. #echanism of action8 They may act by any of the following properties a) ;asoconstriction property b) :oagulant property c) Hygroscopic property which increases their bul2 and aid in plugging disrupted blood vessels.

+%

"ystemic agents 1) Whole blood Ghen there is e cessive blood loss due to hemorrhage ! there are symptoms of hypovolemia shoc2. whole blood transfusion may be indicated.

History of #lood transfusion

+<

 7n 4une of %,,>. -ean(Baptiste 5enis and a surgeon. ?mmere1. transfused blood from a sheep into a %& year old boy who had been bled many times as treatment for fever The patient apparently improved and a successful e perience was reported simultaneously in another patient. Because of two subse@uent deaths associated with transfusion from animals to humans. criminal charges were brought against 5enis. 7n April %,,H. further transfusions in humans were forbidden unless approved by the faculty of medicine in /aris. 7t was not until the %)th century the human blood was recogni1ed as the only appropriate replacement. 7n %)''. "andsteiner and his associates introduced the concept of blood grouping ! identified the ma-or A. B. ! 0 group. 7n %)+). the Rh. group was recogni1ed.

Collection of #lood for #lood transfusion

Before collecting blood from an individual or donor. ma2e sure that the donor is not suffering from any disease which may be transmitted into the blood e.g.8 Hepatitis ! A759. The donor lies down on a bed. A sphygmo(manometer cuff is applied to the upper arm ! in inflated to a pressure of H'mm Hg. '.&ml local anaesthetic solution is in-ected subcutaneously in the antecubital fossa through which %& gauge needles is introduced into medium cubital vein.

++

 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 >&ml of anticoagulant solution. 5uring collection. blood is constantly mi ed with the anticoagulant solution to prevent clotting. A specimen of blood is sent for grouping and cross matching. About =%'ml is ta2en in a single bag. Two types of anticoagulant solutions are usually used to mi with the donor blood. %) CPD solution( contains tri sodium citrate (dehydrate). citric acid (mono hydrate). sodium di hydrogen phosphate (mono hydrate) and de trose mi ed with water. <) CPD !1 solution( with the above mentioned solution adenosine is added to increase the storage life of blood.

)lood storage
9tored in blood ban2 in special refrigerator at controlled temperature of = degree centigrade (,(<:) 7f blood is allowed to come in contact with higher temperature. there is danger of transmitting infection. 5uring storage. the RB: loses their ability of release o ygen to the tissues of the recipient with in > days. GB: is rapidly destroyed. /latelets are destroyed. :lotting factors e.g.8 factor ;. ;777 ! are also destroyed @uic2ly. *actors 77. ;77. 7O ! O7 are stable in ban2ed blood. +=

 9helf life of stored blood in :/5 solution is about +wee2s ! with :/5(%. & wee2s. Besides whole blood. pac2ed red cells are also transfused in certain conditions.

ac7ed red cells8 (Ghole blood is centrifuged at <''' to <&''g for %& to <'minutes or
if the stored blood is allowed to stay idle so that the supernatant plasma is ta2en off and the blood sediment is used for pac2et cells. Transfused specially in patients with chronic anemia

0ther blood substitutes5ivided into < groups

%) /lasma ! its derivatives <) 9ynthetically prepared various solutions 1) lasma . its deri*ati*es

/lasma can be separated from the pac2ed red cells after centrifugation at <''' to <&''g for %& to <' minutes and also by allowing the blood to stay idle for sometime so that the supernatent plasma is ta2en off leaving pac2ed red cell sediments. (resh fro+en plasma8 /lasma removed from fresh blood. which is obtained with in = hours. in rapidly fro1en by immersing solid :0< ! ethyl alcohol mi ture. 9uch plasma is stored at (<':. This process preserves all the coagulation factors. particularly factors ; and ;777. ! useful in the treatment of coagulation deficiencies in liver disease .in haemophilea. :hristmas disease. in defibrination cases. ! vitamin N deficiency.

+&

2)

latelet rich plasma

9uitable for patients suffering from thrombocytopenic purpura /repared by slow centrifugation of fresh whole blood (at the rate of %&' to <'' g for %&(<' minutes) 0ne unit of /R/ raises the platelet count appro imately by >.'''(%'.''' per ml. latelet concentrate 7t is prepared from platelet rich plasma by centrifugation at the rate of %&''g for <'minutes. This is further acidified to a pH of ,.&. The platelet remains active in vitro for =Hhours. 7f the platelet concentrate is stored fro1en. its effectiveness may be e tended to many months of storage. Both platelet rich plasma ! platelet concentrate are used in cases suffering from thrombocytopenic purpura. 3) (i#rinogen 7t is prepared by organic li@uid fractionation of plasma. 7t is stored in dried form ! before using it is made soluble with distilled water. Esed in congenital afibrinogenaemia ! in 57:. 6) Al#umin /repared by repeated fractionation of plasma by organic li@uids and then followed by heat treatment. #ay be stored for several months in li@uid form at =: #ain advantage is that it is free from the danger of transmission of serum hepatitis. +,

 Esed as a volume e pander in patients who cannot tolerate a sodium load (cirrhotic patients) ! in patients with severe albumin loss e.g.8 following severe burn ! in nephritic syndrome. 5isadvantage8 ( e pensive. 8) Cryoprecipitate 7f the fro1en plasma is allowed to bring at a temperature of =:. it will be divided into a white glutinous precipitate ! supernatant plasma. The glutinous precipitate is 2nown as cryoprecipitate. 7t is usually stored at (=': Rich source of factor ;777. so used for in the treatment of hemophilic patients. Also contains a good amount of fibrinogen ! may be used in conditions of hyofibrinogenaemia. B. "ynthetically prepared *arious solution 1) ,extran The bacterium leuconostoc mesenteroides produces this polysaccharide compound to which a yeast e traction is added. This solution induces roulcau formation of red cells. 7t also interferes with the platelet function. so that it may induce abnormal bleeding. 9o this solution should not be used more than %'''ml. 7t also interferes with blood grouping ! cross matching. so blood sample for grouping ! cross matching should be drawn before introducing this solution. Esed to restore plasma volume. in cases of 57:

+>

2) -elatin "ess effective than de tran as plasma volume e pander only +'B of this solution remains in the intravascular compartment after =hours of infusion. 3) Hydroxyl ethyl starch 9HE") 9econd to de tran in its efficiency as a plasma volume e pander 6) (luorocar#ons 7ts main efficacy is that it can bind ! release o ygen rather than merely passively transporting dissolved o ygen. 7t is considered to be a red cell substitute. #ain difficulty is that there is considerable fall in partial pressure of o ygen very @uic2ly. 7n order to maintain ade@uate arterial o ygen content the patient should be 2ept in hyperbaric environment. C4A""I(ICA/I32 3( )4EE,I2- ,I"3!,E!"0 %. Aonthrombocytopenic purpuras Q ;ascular wall alteration (%) 9curvy (<) infections (+) :hemicals (=) Allergy Q 5isorders of /latelet *unction (%) Ienetic defects (Bernard(9oulier 5isease) ( <) 5rugs a).Aspirin b)A9A759 c) Alcohol d) Beta(lactum Antibiotics e) /enicillin f) :ephalosporins +H

(+) Allergy (=) Autoimmune disease (&) Eremia <. Thrombocytopenic purpuras Q /rimary(7diopathic 9econdary (%) :hemicals (<) /hysical agents (radiation) (+) 9ystemic diseases (leu2emia) (=) #etastatic cancer to bone (&) 9plenomegaly Q (,) 5rugs a) Alcohol b) Thia1ide diuretics c) ?strogens d) Iold salts (>) ;asculitis (H) #echanical prosthetic heart valves ()) ;iral or bacterial infections +. 5isorders of coagulation Q 7nherited (%) Hemophilia A (deficiency of factor ;777) (<) Hemophilia B (deficiency of factor 7O) (+) von Gillebrands disease (secondary factor ;777 deficiency) (=) 0thers. Q Ac@uired (%) "iver disease (<) ;itamin deficiency a) Biliary tract obstruction b) #alabsorption c) ? cessive use of broad spectrum antibiotics (+) Anticoagulation drugs +) . . . .
J

a) Heparin b) :oumarin c)Aspirin and A9A759 (=) 57: (&) /rimary fibrinogenolysis . I2HE!I/E, C3A-:4A/I32 ,I"3!,E!"0 The most important inherited bleeding disorders in terms of prevalence and severity are haemophilia A and B (:hristmas disease) and von GillebrandRs disease. #any of the defects present a ha1ard to surgery and to local anaesthetic in-ections. but in general the teeth erupt and e foliate without problems. and non(invasive dental care is safe. HAE'3 HI4IA A0 Haemophilia A is the most common and best(2nown clotting defect. with a prevalence of about & per %'' ''' of the population. 7t is about %' times as common as haemophilia B e cept in some Asians. where fre@uencies are almost e@ual. 7nherited as a se (lin2ed recessive trait. haemophilia affects males. A family history can. however. be obtained in only about ,& per cent of cases. All daughters of an affected male are carriers but sons are normal. 9ons of carriers have a &'8&' chance of developing haemophilia while daughters of carriers have a &'8&' chance of also being carriers. Haemophilia A is due to defective *actor ;777 (antihaemophilia factor. AH*). This is a glycoprotein of several components. including *actor ;7H: (procoagulant that participates in the clotting cascade). ;777R8Ag (von Gillebrand factor. which binds to platelets and is the carrier for *actor ;777:) and ;77R8R:o (ristocetin cofactor. which supports platelet aggregation). 7n haemophilia A only *actor ;777: is reduced. C4I2ICA4 (EA/:!E"J Haemophilia typically becomes apparent in childhood when bleeding into muscles or -oints (Hemarthrosis) follows in-uries. Abdominal haemorrhage may simulate an acute abdomen =' .

Bleeding after dental e tractions is sometimes the first or only sign of mild disease. Bleeding into the cranium. bladder and other sites can cause severe or fatal complications.

C3' 4ICA/I32" Haemorrhage in hemophiliacs is dangerous either because of loss of blood. or because there may be damage to -oints. muscles and nerves. or pressure on vital organs if haemorrhage is internal. Thus compression of the laryn and pharyn following haematoma formation in the nec2 can be fatal. 5ental e tractions or deep lacerations are followed by persistent oo1ing for days or wee2s 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 in-ury (as a result of normal vascular and platelet response) but. after an hour or more. intractable oo1ing or rapid blood loss starts and persists. The severity of bleeding is dependent on two main factors8 i %. The le"el of #actor $%%%C acti"ity& The severity of the disease is variable but correlates well with the *actor ;777 level of the plasma. Aormal plasma contains % unit of *actor ;777 per ml. a level defined as %'' per cent. <. The se"erity of trauma: 9ome very mild haemophiliacs may not bleed e cessively even after a simple dental e traction. so that the absence of post(e traction haemorrhage cannot always be used to e clude haemophilia. #ost will. however. bleed e cessively after more traumatic surgery such as tonsillectomy.

=%

9everity of Haemophilia8 9evere #oderate #ild Aormal B*actor ;777 P% %(& S&(<& S<&

,iagnosis and management of haemophilia A0 ; The typical findings in haemophilia can be summari1ed as follows8 %. <. +. =. /rolonged activated partial thromboplastin time (A/TT). . Aormal prothrombin time (*T). Q Aormal bleeding time. "ow *actor ;7H: but normal ;777R8Ag (von Gillebrand factor) and R8R:o ...... . ...8.
8

(ristocetin cofactor). .

K*actor ;777 assay is re@uired as even the A/TT may be normal in mild haemophilia. 7f bleeding starts or is e pected. treatment consists of replacement of the missing clotting factor. rest and often the use of antifibrinolytic agents. K Rarely. von GillebrandRs disease may mimic haemophilia. The history may help to distinguish them but laboratory testing is essential. K *actor ;777 must be replaced to a level ade@uate to ensure haemostasis. 9ome years ago this was achieved with fresh plasma. or fresh fro1en 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. H7; and various herpes viruses. K /orcine *actor ;777 and genetically engineered *actor ;777 have been considerable advances. Regular prophylactic replacement of *actor ;777 (antihaemophiliac globulin. AH*) is used when possible but necessitates daily in-ections. K AH* is also in short supply and e pensive. and its use may be complicated by antibody formation or viral infections but heat treatment should inactivate H7; that might have been =<

missed in the screening of donors. 7ncreasing reliance is therefore placed on desmopressin and trane amic acid. !eplacement therapy: K Human free1e(dried *actor ;777 concentrate (*actor ;777 fraction. dried) is used when the deficiency is sufficiently severe. This preparation is stable for one year at = T: but once reconstituted should be used without delay. K Aew recombinant *actor ;777 is now available. 7n milder cases (*actor ;777 levels within &(<& per cent of normal) desmopressin and trane arnic acid may be satisfactory and are increasingly used. Haemophilia and *on%ille#rands ,isease0

,ental management in haemophilia A0

5ifficulties in the management of haemophiliacs may include8 %. <. +. =. &. ,. 7. H. ). 5ental neglect necessitating *actor ;777 inhibitors. Ha1ards of anaesthesia. especially nasal intubation. and intramuscular in-ections. Ris2s of hepatitis. and liver disease. H7; infection. Aggravation of bleeding by drugs. An iety. 5rug dependence as a result of chronic pain. fre@uent dental e tractions. Trauma. surgery and subse@uent haemorrhage.

re*enti*e dental care0 ?ducation of patient or parents. and preventive dentistry. should be started as early as possible. 5ental neglect is common and can lead to serious conse@uences. 5ental e tractions are still a ma-or 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. /revention of periodontal disease is also imperative. :omprehensive dental assessment is needed at the age of about %<(%+. to plan for the future and to decide how best to forestall difficulties resulting from overcrowding or misplaced third molars or other teeth. =+

R 'urgery and postoperati"e haemorrhage& 5ental e tractions and surgery are dangerous for haemophiliacs. 9urgery should therefore be carefully planned to avoid complications. All necessary surgery (and other dental treatment) should of course be performed at one operation. Haemophiliacs re@uire the care of specialists of many disciplines and should therefore be treated in Haemophilia Reference :enters. or associated units. Haemophilia cards are issued to confirmed haemophiliacs and give details of the diagnosis and the :entre from which advice can be obtained. Radiographs should be ta2en for any unsuspected disease and to assess whether further e tractions might prevent future trouble.

%n(ections&
"ocal anaesthesia should be avoided in the absence of *actor ;777 replacement. Regional (inferior dental or posterior superior alveolar) bloc2s or in-ections in the floor of the mouth must not be used since they can cause haemorrhage which. by allowing blood to trac2 down to cause airway obstruction. can be life(threatening. Rarely. even submucosal infiltrations have caused widespread haematoma formation. but 7ntraligamentary in-ections may be safe. 7nfiltration anaesthesia may be used with caution and is ade@uate for conservative wor2 in children. but lingual infiltration must be avoided. 7f factor replacement therapy has been given. regional anaesthesia can be used. provided the *actor ;777 level is maintained above +' per cent. but infiltration is still preferable. 7ntravenous mida1olam or relative analgesia can be used. 7ntramuscular in-ections should be avoided unless replacement therapy is being given. as they can cause large haematoma. 0ral alternatives are in any case satisfactory in most instances.

Conser*ati*e dentistry0 ):onservative treatment of the primary dentition and sometimes of the permanent dentition may be carried out without anaesthesia. ==

K 7f conservative treatment is not tolerated without anaesthesia. papillary or intraligamentary infiltration may achieve sufficient analgesia and is unli2ely to cause serious bleeding. K 9oft tissue trauma must be avoided and a matri band may help prevent gingival laceration. However. care must be ta2en not to let the matri band cut the periodontal tissues and start gingival bleeding. K A rubber dam is also useful to protect the mucosa from trauma but the clamp must be carefully applied. K High speed vacuum aspirators and saliva e-ectors must be used with caution in order to avoid production of haematomas. Trauma from the saliva e-ector can be minimi1ed by resting it on a gau1e swab placed in the floor of the mouth. Endodontics0 KRoot canal treatment may obviate the need for e tractions and can usually be carried out without special precautions other than care to avoid reaming through the ape . K Topical application of %' per cent cocaine to the e posed pulp is the choice for vital pulp e tirpation. However. in severe haemophilia. bleeding from the pulp and periapical tissues can be persistent and troublesome. eriodontal treatment0 7n all but severe haemophiliacs scaling can be carried out under antifibrinolytic cover. /eriodontal surgery necessitates factor replacement. 3rthodontics0 There is no contraindication to the movement of teeth in haemophilia. However. there must be no sharp edges to appliances. wires etc.. which might traumati1e the mucosa. 'inor surgery0 K?ndotracheal 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. K An oral late cuffed endotracheal tube is recommended to minimi1e 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. K A *actor ;777 level of between &' and >& per cent is re@uired for dental e tractions. AH* may also need to be given postoperatively but many patients can be managed with antifibrinolytic agents given during the subse@uent %' days. 7f oral bleeding recurs =&

postoperatively. *actor ;777 must be given. 9ome advise the administration of a further single dose of *actor ;777 as a routine on the fourth or fifth postoperative day. However. this should be unnecessary if ade@uate *actor ;777 has been given preoperatively. KAntifibrinolytics significantly reduce *actor ;777 re@uirements. Trane amic acid (:y2lo2apron) is used in a dose of % g (+' mgM2g) orally. four times daily starting <= hours preoperatively. Antifibrinolytics must not be used systemically where residual clots are present. for e ample in the urinary tract or intracranially. 7n haemophiliacs. the urine should therefore be e amined preoperatively for haematuria. K Trane amic acid used topically significantly reduces bleeding. Ten ml of a & per cent solution used as a mouth rinse for < minutes. four times daily for > days. is recommended. This solution can be made up by diluting %' per cent trane amic acid solution with sterile water. K 5esmopressin (deafflino(H(5 arginine vasopressin8 55A;/) is a synthetic analogue of vasopressin which induces the release of *actor ;777:. von GillebrandRs factor (vG*) and tissue plasminogen activator (t/A) from storage sites in endothelium. Iiven as an intravenous infusion ('.+('.& ugM2g -ust before surgery. and repeated %< hourly if necessary for up to = days). desmopressin can temporarily correct the haemostatic defect in mild haemophilia. K 5esmopressin may be useful for patients with *actor ;777 inhibitors. and is also increasingly widely used. as mentioned earlier. for the management of mild haemophiliacs for such purposes as e tractions. 7t is now available for subcutaneous or intranasal use when doses of +'' mg appear as effective as '.< mgM2g i.v. As desmopressin also causes release of plasminogen activator. trane amic acid should also be given. K 5esmopressin may cause facial flushing and slight tachycardia but the chief adverse effect is tachyphyla is ( declining response on repeated in-ection. 4ocal measures0 are also important to protect the operation area and minimi1e the ris2 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. 9uturing (though theoretically unnecessary) is desirable to stabili1e gum flaps and to prevent postoperative disturbance of wounds by eating. Aon(resorbable sutures are preferred and should be removed at =(> days. 9uturing carries with it the ris2. if =,

there is postoperative bleeding. of causing blood to trac2 down towards the mediastinum with danger to the airway. However. such an eventuality is an indication of inade@uate preoperative replacement therapy. although complications of this sort can result from the presence of *actor ;777 inhibitors when postoperative haemostasis is less predictable. 7n the case of difficult e tractions. 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 trac2 and endanger the airway. The buccal approach to lower third molars is therefore safer. #inimal bone should be removed and the teeth should be sectioned for removal where possible. The pac2ing of e traction soc2ets is unnecessary if replacement therapy has been ade@uate but some advice the pac2ing of a small amount of o idi1ed cellulose soa2ed in trane amic acid into the depths of the soc2ets. 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. "ocal haemostasis can be aided by collagen. Ielfoam or 9urgicel inserted into e traction soc2ets. and by cyanoacrylate or fibrin glues. re*ention of infection0 Antimicrobials such as oral penicillin ; <&' mg four times daily should be given postoperatively for a full course of > days to reduce the ris2 of secondary haemorrhage. 7nfection also appears to induce fibrinolysis. /ostoperatively. a diet of cold li@uid and minced solids should be ta2en for up to %' days. :are should be ta2en to detect haematoma formation which may manifest itself by swelling. dysphagia or hoarseness. The patency of the airway must always be ensured. 'a<or surgery0 Before ma-or surgery the patient is assessed by haemostatic screening (A*TT. /T. and platelet) count). *actor ;777 assay. specific antibody test. fibrinogen estimation. hepatitis B. : and H7; 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. =>

surgery is best earned out on Thursdays and *ridays. since bleeding is most li2ely on the day of operation or from = to %' days postoperatively.

All surgical procedures must be covered with AH* which is given % hour preoperatively. the dose of AH* given before operation depends both on the severity of

haemophilia and the amount of trauma e pected . *actor ;777 is effective only for about %< hours and therefore must be given regularly at least twice(daily postoperatively for ma-or surgery. Trauma to the head and nec*: Haemophiliacs with head and nec2 in-uries are at ris2 from bleeding into the cranial cavity or into the fascial spaces of the nec2. They should. therefore. be given factor replacement to a level of %'' per cent prophylactically after a head or facial trauma. 7f there are lacerations that need suturing. a minimum level of *actor ;777 of &' percent is re@uired at the time. with further cover for + days.

3ther considerations0
+aemophiliacs ,ith inhibitors& Between & and <' per cent of haemophiliacs who have had multiple infusions. and a few who have not. develop inhibitory antibodies. which reduce the activity of *actor ;777. These problems are most common in severe haemophilia. Bleeding episodes are not more fre@uent when inhibitors are present but are more difficult to control. Two types of inhibitor are 2nown high and low litre inhibitors. 7n 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. 7f the concentration of inhibitors is low *actor ;777 may be effective for =(& days or longer if immunosuppressive therapyR such as prednisolone or =H

cyclophosphamide is given. 7n those with higher concentrations of inhibitors. monoclonal antibody(purified *actor ;777 infusion or recombinant *actor ;777 can often be effective. Human *actor ;777 7nhibitor Bypassing *ractions (*?7BA) are also availableJ these are usually either non(activated prothrombin comple concentrates (/::) or activated prothrombin comple concentrates (A/::) which act by activating *actor O directly bypassing the intrinsic pathway of blood clotting. The danger with these products is of uncontrolled coagulation with thromboses. 7n many cases. desmopressin is an effective alternative and antifibrinolytics may help. or immunosuppression may be re@uired. +epatitis, infection ,ith +%$ and li"er disorders& Haemophilics are at ris2 from viral hepatitis and infection with H7;. #any patients treated before blood products were screened for hepatitis B or heat(treated against H7; are particularly at ris2. Hepatitis : and 5 infection. however. are increasingly prevalent. -leeding aggra"ated 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. :odeine and paracetamol are safer alternative analgesics. n.iety& #any haemophiliacs are acutely an ious about dental treatment. ?motional 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.

CH!I"/'A" ,I"EA"E 9HAE'3 HI4IA ))0

=)

:hristmas disease (*actor 7O deficiency) is clinically identical to haemophilia A and inherited in the same way. but it is about one(tenth as common as haemophilia A. *emale carriers often have a bleeding tendency.

,ental management of haemophilia )0

The earlier comments on dental management in haemophilia A apply e@ually to patients with haemophilia B. but *actor 7O replacement is needed before surgery and desmopressin is not used. Human dried *actor 7O concentrate is supplied as a powder to be reconstituted with sterile distilled water for intravenous administration. A dose of <' units *actor 7O per 2g body weight is used intravenously 7 hour preoperatively. The standard preparation may also contain *actors 77. ;77 and O. *actor 7O is more stable than *actor ;777. 7ts half(life is often up to < days. so that replacement therapy can sometimes be given at longer intervals than in haemophilia A. V32 %I44E)!A2,=" ,I"EA"E0 ;on GillebrandRs disease (pseudohaemophilia) is the most common inherited bleeding disorder and affects about % B of the population. 7t is caused by a deficiency of. or defect in. von Gillebrand factor (vG*). The vG*. synthesi1ed in endothelium and mega2aryocytes. normally acts as a carrier for *actor ;777 protecting it from proteolytic degradation. A deficiency in vG* thus leads to a low *actor ;777 concentration in the blood. vG* also bridges between platelets and damaged endothelium. Thus the bleeding tendency in von GillebrandRs disease results both from a clotting defect and a defect in platelet function. ;on GillebrandRs disease not only affects females as well as males but the clinical presentation usually differs from haemophilia A .

&'

The common pattern is bleeding from mucous membranes. with purpura of mucous membranes and the s2in. Iingival haemorrhage is more common than in haemophilia. ? cessive 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 vG* results in poor platelet adhesion after trauma. /latelets usually fail to aggregate in the presence of ristocetin so that. unli2e haemophilia. purpura is common and the bleeding time is prolonged but the best assay is the ristocetin cofactor assay.

;on GillebrandRs disease is thus characteri1ed by a prolonged bleeding time. usually a prolonged A/TT. low levels of von GillebrandRs factor (*actor ;777R8Ag). and low *actor ;777: and ;777R8R:o (ristocetin cofactor) levels.

There are various types of von GillebrandRs disease and the severity varies from patient to patient and from time to time. 9ome patients have a clinically insignificant disorder. while others have *actor ;777 levels low enough to cause severe clotting defects as well as a prolonged bleeding time. However. the severity does not correlate well with the *actor ;777 level. /regnancy and the contraceptive pill may cause transient amelioration. ;on GillebrandRs disease has over <' variants but H'B have type 7 and nearly <'B have type 77 disease. 7t is usually inherited as an autosomal dominant but a severe form of the disease may be inherited as a se (lin2ed recessive trait li2e true haemophilia. Rarely. von GillebrandRs disease may be ac@uired. particularly in patients with autoimmune or lymphoproliferative diseases.

,ental management in *on %ille#rand=s disease0 Aspirin and A9A75s should be avoided. 7n most patients with von GillebrandRs disease. the haemostatic defect can be controlled with desmopressin. now mainly given via a nasal spray. The chief e ceptions are. first. type 77B disease. in which desmopressin is contraindicated because it stimulates release of dysfunctional von Gillebrand factor which leads. in turn. to platelet aggregation and severe but transient thrombocytopenia. 9econd. it is also contraindicated in type 777 .disease. &%

where so little von Gillebrand factor is formed that essentially the same management is re@uired as for haemophilia A. However. since *actor ;777 has a prolonged half(life. less fre@uent infusions may be re@uired. Thus type 7 von GillebrandRs disease can be treated with desmopressin but types 77 and 777 re@uire clotting factor replacement. Hereditary haemorrhagic telangiectasia. mitral valve prolapse. or *actor O77 deficiency may be associated and may re@uire to be considered in the management plan. 3/HE! C32-E2I/A4 C3A-:4A/I32 ,E(EC/"0 *actor O7 deficiency (plasma thromboplastin antecedent deficiency) is one of the more common other congenital coagulation defects and is sometimes 2nown as haemophilia :. Any of the other clotting factors can be deficient and all may be associated with a haemorrhagic tendency. e cept *actor O77 deficiency (despite the prolonged clotting time and A/TT in this defect there is actually a tendency to thromboses). #ost are uncommon or rare defects. *resh fro1en plasma will usually correct most of these coagulation defects. but local haemostatic measures should also be applied. AC>:I!E, C3A-:4A/I32 ,E(EC/"0 Ac@uired haemorrhagic disorders are much more prevalent than the congenital diseases but. e cept in anticoagulant therapy or liver disease. are usually less severe. 7mportant causes include8 %. Anticoagulant therapy. <. ;itamin N deficiency or malabsorption. . +. "iver disease (deficiency of *actor O77). =. 5isseminated intravascular coagulation. &. *ibrinolytic states. ,. Amyloidosis (deficiency of *actor O). >. Autoimmune disorders (deficiency of *actor ;777) Aevertheless. some of those with clinical bleeding tendencies do not have a defect detectable by current laboratory methods.

&<

Anticoagulant treatment0
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. Aevertheless. severe blood loss can occur. :oumarins such as warfarin are given orally and antagoni1e the action of vitamin N so that the prothrombin and activated partial thromboplastin times are prolonged. The effects are delayed for H(%< hours. are ma imal at +, hours. but persist for >< hours. Aicoumalone and phenindione are seldom used. 0ral anticoagulants are teratogenic. :oumarin anticoagulant therapy should maintain a prothrombin time of <(< %M< times the control (control %%(%& seconds). or a thrombotest of &(<' per cent.

Important Conditions for &hich Anticoagulants may #e used0 K Atrial fibrillation . K :erebral Thrombosis K 5eep vein thrombosis K ?mboli1ation secondary to myocardial infarction K Heart valve replacements KRenal dialysis. prothrombin times are often now recorded as the international normali1ed ratio (7AR). a ratio of <(+ being the usual therapeutic range for deep vein thrombosis. and up to =.& being re@uired for patients with prosthetic heart valves. . Heparin is not given orally but by in-ection and acts immediately. mainly by inhibiting the thrombin(fibrinogen reaction. The prothrombin. activated partial thromboplastin UA/TT) and thrombin times are therefore prolonged. #ost patients are monitored with the A/TT. /latelet counts should also be monitored if heparin is used for more than & days. since thrombocytopenia &+

can result. The anticoagulant effect of heparin is usually lost within less than , hours of stopping heparin. "ow molecular weight heparins. which include dalteparin. eno aparin and tin1aparin. 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. Aeglect of this important point has led to rebound thrombosis which has damaged prosthetic cardiac valves and even caused thrombotic deaths.

,ental management of patients on oral 9coumarin) anticoagulation0

The prothrombin time (/T) 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 e pressed as the ratio of the /T 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 /T. an 7AR has been devised. this being the /T ratio (patientRs /TMcontrol /T) that would have been obtained if an international reference thromboplastin type ,>M=' had been used. 7n a person with a /T within the normal range. the 7AR is appro imately %. 7t is important to recogni1e that the 7AR is valid only for patients on stable anticoagulant therapy. /atients on coumarin anticoagulants should not have their medication stopped or changed before dental treatment e cept under special supervision. #inor surgery (simple e tractions of two or three teeth) may be carried out safely with no change in anticoagulant treatment if the prothrombin rime is within %.&(+ times normal (7AR up to +.&). Regional bloc2s should be avoided. 9urgery should be as atraumatic as possible. and a little haemostatic material (e.g. o idi1ed cellulose or fibrin). but is not essential. /atients re@uiring ma-or oral surgery are best admitted to hospital =H hours before the operation. as are patients with 7AR above +.& and. with the agreement of the &=

clinician in charge. anticoagulation may need to be modified. 7f anticoagulants are to be continued. vitamin N should preferably be avoided as it ma2es subse@uent anticoagulation difficult. 7f postoperative bleeding occurs. vitamin N may be given to counteract the coumarins. 7f the use of vitamin N cannot be avoided. only %' mg should be given. 7n an emergency an antifibrinolytic agent (trane amic acid) can be used to control haemorrhage. /atients on oral anticoagulants are especially at ris2 from haemorrhage under the following circumstances. %. <. 7rregular tablet ta2ing. "iver disease or obstructive -aundice. which impairs vitamin N metabolism or

absorption. +. /rolonged antimicrobial therapy (a1ole antifungals. penicillins. metronida1ole. erythromycin. =. cephalosporins). "i@uid paraffin which leads to loss of vitamin N (theoretically).

&. Ese of protein(binding drugs which displace the anticoagulant from plasma proteins and enhance its effect. e.g. aspirin. a1ole antifungals and sulphonamides. :o(trimo a1ole. which contains a sulphonamide. and a1oles. even as oral gels. may therefore be contraindicated. ,. Ese of aspirin and other non(steroidal anti(inflammatory agents which can cause gastric bleeding and also interfere with platelet function. >. Githdrawal of barbituratesJ this decreases the brea2down of anticoagulants. Ender such circumstances the thrombotest should be repeated within <= hours of surgery.

,ental management of patients on heparin anticoagulation0

o The effect of heparin is best assessed by the thrombin time. which is usually maintained at +(= times normal (control %'(%< seconds). "ow dose heparin therapy such as R#inihepR (used to reduce postoperative complication of deep vein thrombosis) may have little effect on the thrombin time. A/TT or on postoperative bleeding. o Heparin is given intravenously and its use is therefore restricted to inpatients. 7t has an immediate effect on blood clotting but acts for only =(, hrs. so that no specific treatment is needed to reverse its effect. This can be achieved immediately during &&

an emergency by intravenous protamine sulphate given in a dose of % mg per %'' 7E heparin. Esually there is no need to interfere with anticoagulant treatment for simple e tractions. o 9urgery can safely be carried out after ,(H hours. when the effects of heparini1ation have ceased. "ow molecular weight heparins act for up to <= hours. however. 7n renal dialysis patients surgery is best carried out on the day after dialysis as the effects of heparini1ation have then ceased and there is ma imum benefit from dialysis. 7t should be remembered that the condition for which anticoagulant therapy is being given. especially prosthetic heart valves. may also affect dental management. Vitamin ? deficiency and mala#sorption0 o ;itamin N is ta2en in with the diet and also synthesi1ed by the gut flora. 7t 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 N is used for the synthesis of *actors 77 (prothrombin). ;77. 7O and O. o Haemorrhagic disease may. therefore. result from too little vitamin N reaching the liver. particularly as a result of obstructive -aundice or malabsorption. Alternatively. vitamin N metabolism may be impaired by anticoagulants or severe liver disease. 7n the last. many haemostatic functions are severely(impaired and vitamin N is of little or no value.

,ental aspects of *itamin ? deficiency0

5ental management in vitamin N deficiency may be complicated by (a) the clotting defect and (b) the underlying disorder. particularly obstructive -aundice. 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 N can be given if surgery is urgent. /hytomenadione (&(<& tng) is the most potent and rapidly acting form and should preferably be given intravenously to avoid intramuscular in-ection. o The prothrombin time should be monitored after =H hours. and. if the defect has not been corrected by then. this suggests parenchyma) liver disease. &,

Clotting ,efects in*ol*ing Vitamin ?0 K"ac2 of vitamin synthesis in gut8 Broad spectrum antibiotics used for prolonged periods or inpatients on /arenteral feeding. K/oor Absorption #alabsorption 9yndromes 0bstructive 4aundice K *ailure of utili1ation 0ral anticoagulant treatment "iver failure 4i*er disease0 "iver disease is an important cause of bleeding disorders. The haemostatic defects in liver failure include (a) impaired vitamin N metabolismJ (b) increased fibrinolysisJ (c) failure of synthesis or increased consumption of normal clotting factorsJ (d) synthesis of abnormal clotting factorsJ and (e) thrombocytopenia. Haemorrhage can be severe and difficult to manage because of the comple ity of these defects. Antitibrinolytic treatment and fresh fro1en plasma may sometimes be effective. 7f there is an obstructive element to the disease vitamin N. may be effective. but only if parenchymaV disease is mild. (i#rinolytic drugs and states0 *ibrinolytics. such as strepto2inase. alteplase. anistreplase and uro2inase. and local activation of plasmin by infection for e ample. may cause abnormal bleeding. 5ental surgery should be deferred where possible in patients on fibrinolytic therapy. Ac@uired haemophilia0 This rare disorder is due to circulating antibodies to *actor ;777 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. 9pecialist haematological attention is re@uired before any invasive dental treatment is considered. &>

3ther disorders associated &ith #leeding tendencies0 These include the following8 %. /olycythaemia vera. .R <. #yelofibrosis. leu2aemia or lymphoma. +. :hronic renal failure. =. :yanotic congenital heart disease. &. Iram(negative shoc2. ,. After massive transfusions. >. Antibodies to clotting factors .H. Head in-uries.

&H