Introduction Bleeding disorders is a general term for a wide range of medical problems that lead to poor blood clotting

and continuous bleeding. Doctors also call them with such terms as coagulopathy, abnormal bleeding and clotting disorders. When someone has a bleeding disorder they have a tendency to bleed longer. The disorders can result from defects in the blood vessels or from abnormalities in the blood itself. The abnormalities may be in blood clotting factors or in platelets. Blood clotting, or coagulation, is the process that controls bleeding. It changes blood from a liquid to a solid. It's a comple process involving as many as !" different plasma proteins, or blood clotting factors. #ormally, a comple chemical process occurs using these clotting factors to form a substance called fibrin that stops bleeding. When certain coagulation factors are deficient or missing, the process doesn't occur normally. History Bleeding disorders have been recogni$ed all the way bac% to ancient times. Though not named, they were referenced e tensively. In the Talmud, a collection of &ewish 'abbinical writings from the !nd century (D, it was written that male babies did not have to be circumcised if two brothers had already died from the procedure. ( )!th century (rab physician named (lbucasis also wrote about a family in which males died of e cessive bleeding from minor in*uries. Bleeding disorders li%e hemophilia have been recogni$ed for hundreds of years to +run in+ families. In the ,.-., the transmission of hemophilia from mothers to sons was first described in the early ).""s. In )."/, a 0hiladelphia physician named Dr. &ohn 1onrad 2tto wrote an account of +a hemorrhagic disposition e isting in certain families.+ 3e recogni$ed that a particular bleeding condition was hereditary and affected males. 3e traced the disease bac% through three generations to a woman who had settled near 0lymouth, #ew 3ampshire, in )4!". The word +3emophilia+ first appeared in a description of a bleeding disorder condition at the ,niversity of 5urich in ).!..

A Royal Disease 3emophilia has often been called the +'oyal Disease.+ This is because 6ueen 7ictoria, 6ueen of 8ngland from )./4 to )9"), was a carrier. -he passed the disease on to several royal families. 3er eighth child, :eopold, had hemophilia and suffered from frequent hemorrhages, which were reported in the British ;edical &ournal in ).<.. :eopold died of a brain hemorrhage at the age of /), but not before he had children. 3is daughter, (lice, was a carrier and her son, 7iscount Trematon, also died of a brain hemorrhage in )9!..

Nicholas and Alexandra 3emophilia played an important role in the 'ussian 'oyal family, as well. Two of 6ueen 7ictoria's daughters, (lice and Beatrice, were carriers of hemophilia. They passed the disease on to the -panish, =erman and 'ussian royal families. (le andra, 6ueen 7ictoria's granddaughter, married #icholas, the Tsar of 'ussia in the early )9""'s. (le andra was a carrier of hemophilia. 3er first son, (le ei, was a

hemophiliac. #icholas and (le andra were pre>occupied by the health problems of their son at a time when 'ussia was in turmoil. ( mon%, 'asputin, gained great influence in the 'ussian court, partly because he was the only one able to help the young Tsarevich (le ei. 3e used hypnosis to relieve (le ei's pain. The use of hypnosis not only relieved pain, but may have also helped slow or stop the boy's hemorrhages. The illness of the heir to the Tsar's throne, the strain it placed on the 'oyal family, and the power wielded by the mad mon% 'asputin were all factors leading to the 'ussian 'evolution of )9)4. In )9)<, the ?@>year old faith>healer 'asputin was %illed at 0etrograd at the hands of a group of noblemen bent on ridding 'ussia of the mon%'s corrupting influence on #icholas II and (le andra. Finding the Cause In the !"th century doctors loo%ed for the cause of e cessive bleeding. ,ntil then, they had believed that the blood vessels of hemophiliacs were simply more fragile. )9!@ (lthough it is probably the most common hereditary bleeding disorder Aaffecting appro imately )B to !B of the populationC, von Willebrand disease was not recogni$ed until )9!@. )9/"s Doctors loo%ed at defective platelets as the li%ely cause of bleeding disorders and hemophilia. Then in )9/4, 0ate% and Taylor, two doctors at 3arvard, found they could correct the clotting problem by adding a substance which came from the plasma in blood. They called it +anti>hemophilic globulin.+ )9?? 0avlos%y, a doctor from Buenos (ires, (rgentina, did a lab test which showed that blood from one hemophilic patient could correct the clotting problem in a second and vice>versa. 3e had stumbled upon two persons with hemophilia each with a deficiency in different proteins > factor 7III and factor ID. This led to the recognition in )9@! of hemophilia ( and hemophilia B as two distinct diseases. 3

Identifying Clotting Factors )9<"s In the )9<"s the clotting factors were identified and named. (n article in #ature in )9<? described the clotting process in detail. The interaction of the different factors in blood clotting was named the +coagulation cascade.+ In the )9@"s and early )9<"s, hemophilia and other bleeding problems were treated with whole blood or fresh plasma. ,nfortunately, there wasn't enough of the factor 7III or ID proteins in these blood products to stop serious internal bleeding. ;ost people with severe hemophilia and some people with mild or moderate hemophilia died in childhood or early adulthood. The most common causes of death were bleeding in vital organs, especially the brain, and bleeding after minor surgery or after an in*ury. Those who survived were usually crippled by the long>term effects of repeated hemorrhages into the *oints. The pressure of massive bleeding into *oints and muscles made hemophilia one of the most painful diseases %nown to medicine. Then, in the )9<"s, cryoprecipitate was discovered by Dr. &udith 0ool. 1ryoprecipitate is the factor>rich component of blood, containing concentrated factor 7III. Dr. 0ool found that the sludge on top of thawing plasma was rich in factor 7III. Eor the first time, enough factor 7III clotting factor could be infused to control serious bleeding. 8ven surgery became possible. This medical brea%through ended the need for high>volume whole plasma transfusions for persons with hemophilia )94"s Then, later in the )9<"s and early )94"s, concentrates containing factor 7III and ID began to be available. These free$e>dried powdered concentrates could be %ept at home and used as needed. They revolutioni$ed hemophilia care. 0ersons with hemophilia were now independent of hospitals. They could travel, hold steady *obs and hope to lead normal lives. Tragically, these same blood products carried blood> borne viruses li%e hepatitis 1 and 3I7. ;any persons with hemophilia were infected. 4

)99"s In the )99"s, modern treatment, using safer factor concentrates, has again improved the outloo%. ;ost children born with hemophilia today can loo% forward to long, healthy, active and productive lives. 'ecent progress includesF G #ew clotting factor products and drugs such as desmopressin acetate Aalso %nown as DD(70, used to treat mild>to>moderate hemophilia ( and von Willebrand diseaseC G #ew, synthetic Anot derived from plasmaC clotting products that ta%e advantage of recombinant technologies G Better screening methods to detect and remove viruses and other agents from factor concentrates and blood products G Improved surgical options G (dvanced genetic testing methods G ;edically supervised home>infusion therapy G 0rophylactic treatment HEMOSTASIS I. PLATELETS: 2riginF 0latelets are developed in bone marrow from mega%aryocyte. 0luripotent stem cell 0romega%aryoblast ;ega%aryoblast ;ega%aryocyte

 0latelets 1. FUNCTION ! ). Damage to vessel releases @3T, TD(! !. 0latelet adhesion, platelet aggregation and platelet plug formation. /. 0E/ > which helps in clotting. ?. 3elps in clot retraction @. 0D=E > 3elps in growth and multiplication of vascular endothelial cells, vascular submucosal cells and fibroblasts required for repair of damaged walls. :ife spanF 4>)? days -ite of destruction F -pleen #ormal countF ).@ > ?.@ lac%s H cc Increase in countF Thrombocytosis Decrease in countF Thrombocytopenia Decrease in platelet count below ?","""is associated with hemorrhagic disorders. " a# $hysiological %ariations ! ). -easonal > 1ount is more during winter season. !. 0regnancy > 1ount decrease /. 8 ercise, e citement, in*ection of adrenaline, high altitude > Increased count. &. $athological %ariations ! ). Increased platelet count seen after splenectomy idiopathic. !. Decreased platelet count is seen in 7iral infection Idiopathic (plastic anaemia

II. COA'U(ATION ! 0rimary hemostasis is platelet plug formation. thrombin. 1lotting EactorsF I. II. III. I7. 7. 7I. 7II. 7III. ID. D. DI. DII. DIII. Eibrinogen 0rothrombin Tissue thromboplastin 1alcium :abile factor > 0roaccelerin Does not e ist -table factor > 0roconvertin (II= or (3E 1hristmas factor -tuart 0rower factor 0T( > 0lasma thromboplastin antecedent 3ageman factor Eibrin stabili$ing factor -econdary hemostasis is coagulation. 1oagulation is the convertion of fibrinogen to fibrin in the presence of

The coagulation proteins are divided into / groups on the basis of their biochemical properties and function. I. II. III. I. II. III. 7itamin I dependent coagulation proteins 1ontact proteins Thrombin sensitive proteins These are prothrombin, factor 7II, factor ID, and Eactor D. synthesi$ed in liver. These are DII, pre%alli%rein, factor DI and 3;W1. They are produce in liver. They are fibrinogen, 7, 7III, DIII. These are

!C There are / essential steps in coagulation. ). Eormation of prothrombin activator in response to vessel or tissue damage.

!. 1onversion of prothrombin to thrombin /. 1onversion of fibrinogen to fibrin )NTH* I OF $ROTHRO+,IN ACTI%ATOR! ! mechanisms. ). 8 trinsic mechanism !. Intrinsic mechanism -# *.TRIN IC +*CHANI +! It is so called because some factors necessary for the formation of 0T( are present outside i.e. in the tissue. There are / important steps. ). Traumati$ed tissue liberates tissue thromboplastin which includes phospholipids and glycoproteins. !. Eactor D is activated in the presence of factor 7II, phospholipids and calcium. 7II J III J 1aJJ D /. Eormation of 0T( from Da. In the presence of factor 7, 1a JJ and phospholipids Da forms prothrombin activator. Tissue trauma Tissue thromboplastin J glycoprotein J phospholipids 1aJJ and 7II D Da 1aJJ 7 0hospholipids 0T( Da Da

 0T Thrombin When the tissue trauma is e tensive 1lotting occurs in )@ seconds. INTRIN IC +*CHANI +! It is named so because all the factors necessary for the formation of 0T( are present in the blood. The mechanism is %nown as ;acfarian's 1ascade hypothesis. (s a resulting of in*ury blood is e posed to connective tissue. ne t active en$yme and thus so on. Thus sequence of changes occurs. ). Trauma to vessel wall causes factor DII. 3;WI and 0I to form a comple with vascular and subendothelial collagen. (fter binding to 3;WI inactive factor DII is converted to active DII ADIIaC. !. DIIa activates DI to DI a /. DIa activates ID to IDa in presence of calcium. ?. IDa along with 7II, 1aJJ, platelet phospholipids converts D to Da. @. Da in the presence 7 1aJ! and platelet phospholipid forms 0T(. <. 8 cept in the first two steps 1a is necessary for clotting. Eormation of 0T( by intrinsic mechanism occurs in ?>. minutes. 2nce 0T( formed clot is formed in )">/" seconds. Eibrin monomer forms the fibrin threads, these threads are not cross lin%ed. 3ence clot is wea%. In the presence of factor DIII a firm polymer is formed. I#T'I#-I1 -urface contact DII DIIa DI DIa Tissue factor 9 8DT'I#-I1 Tissue damage DIIa converts 0I to %alli%rein activates conversion of DII to DIIa. This is positive feed bac% mechanism. Inactive precursor is converted to active en$yme which acts on the ne t precursor to form

 ID 1aJJ 1aJJ 7III 0hospholipid D 1aJJ 7 AIIC 0rothrombin Thrombin AIIaC DIII DIIIa Eibrinogen Eibrin RO(* OF THRO+,IN! ). 1onverts fibrinogen to fibrin !. (ctivates factor 7III /. (ctivates factor 7 ?. (ctivates factor DIII @. 0romotes aggregation of platelets this increases available phospholipids. Thrombin intensifies the reactions promoting local clotting but only for short time i.e. until a firm clot is formed. Then it inactivates clot formation spread of clot does not occur because .@ > 9"B of thrombin is absorbed 'emaining thrombin combines with antithrombin III which inactivates it. 1omposition of 1lotF It contains fibrin, threads spreading in all directions in which 'B1, WB1, platelets and plasma are entrapped. 10 Eibrin -tabili$ed Da 0hospholipid 7II IDa

1lot 'etractionF 1lot retracts to ?"B of original si$e in /"><" minutes and becomes tough. This is because of contractile proteins present in the platelets. (s clot retracts, edges of bro%en vessels are pulled together. achieved. BLEEDING DISORDERS He/o0hilia AAEactor 7III DeficiencyC 1hat Is It2 3emophilia is a bleeding disorder caused by a deficiency in one of the blood clotting factors. 3emophilia ( Aoften called classic hemophiliaC accounts for about ."B of all hemophilia cases. It is a deficiency in clotting factor 7III. 3emophilia ( is a hereditary disorder in which the clotting ability of the blood is impaired and e cessive bleeding results. -mall wounds and punctures are usually not a problem, but uncontrolled internal bleeding can result in pain and swelling and permanent damage, especially to *oints and muscles. -everity of symptoms can vary and severe forms become apparent early on. 0rolonged bleeding is the hallmar% of hemophilia ( and typically occurs when an infant is circumcised. (dditional bleeding manifestations ma%e their appearance when the infant becomes mobile. ;ild cases may go unnoticed until later in life when there is e cessive bleeding and clotting problems in response to surgery or trauma. Internal bleeding may happen anywhere, and bleeding into *oints is common. The incidence of hemophilia ( is one in )",""" live male births. (bout )4,""" (mericans have hemophilia. Women may have it, but it's very rare. With treatment and management, the outcome is good. ;ost men with hemophilia are able to lead relatively normal lives. Thus ultimately haemostasis is

11

Inheritance $attern 3emophilia ( is caused by an inherited se >lin%ed recessive trait with the defective gene located on the D chromosome. Eemales are carriers of this trait. Eifty percent of the male offspring of female carriers have the disease, and @"B of their female offspring are carriers. (ll female children of a male with hemophilia are carriers of the trait. 2ne third of all cases of hemophilia ( occur when there is no family history of the disorder. In these cases, hemophilia develops as the result of a new or spontaneous gene mutation. =enetic counseling may be advised for carriers. Eemale carriers can be identified by testing. A woman is definitely a hemophilia carrier if she is: G the biological daughter of a man with hemophiliaK G the biological mother of more than one son with hemophiliaK G the biological mother of one hemophilic son who has at least one other blood relative with hemophilia. A woman may or may not be a hemophilia carrier if she is F G the biological mother of one son with hemophiliaK G the sister of a male with hemophiliaK G an aunt, cousin or niece of an affected male related through maternal tiesK G the biological grandmother of one grandson with hemophilia. The only way a woman could ever have hemophilia is if her father has it and her mother carries the gene. Women who are carriers can also be symptomatic carriers, whereby they do e perience factor deficiencies. y/0to/s 3 Diagnosis 3emophilia is caused by several different gene abnormalities. The severity of the symptoms of hemophilia ( depends on how a particular gene abnormality affects the activity of factor 7III. When the activity is less than ) percent of normal, episodes of severe bleeding occur and recur for no apparent reason.

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-ymptoms includeF G Bruising G -pontaneous bleeding G Bleeding into *oints and associated pain and swelling G =astrointestinal tract and urinary tract hemorrhage G Blood in the urine or stool G 0rolonged bleeding from cuts, tooth e traction, and surgery 0eople whose clotting activity is @ percent of normal may have only mild hemophilia. They rarely have unprovo%ed bleeding episodes, but surgery or in*ury may cause uncontrolled bleeding, which can be fatal. ;ilder hemophilia may not be diagnosed at all, although some people whose clotting activity is )" to !@ percent of normal may have prolonged bleeding after surgery, dental e tractions, or a ma*or in*ury. =enerally, the first bleeding episode occurs before ). months of age, often after a minor in*ury. ( child who has hemophilia bruises easily. 8ven an in*ection into a muscle can cause bleeding that results in a large bruise AhematomaC. 'ecurring bleeding into the *oints and muscles can ultimately lead to crippling deformities. Bleeding can swell the base of the tongue until it bloc%s the airway, ma%ing breathing difficult. ( slight bump on the head can trigger substantial bleeding in the s%ull, causing brain damage and death. ( doctor may suspect hemophilia in a child whose bleeding is unusual. ( laboratory analysis of blood samples can determine whether the child's clotting is abnormally slow. If it is, the doctor can confirm the diagnosis of hemophilia ( and can determine the severity by testing the activity of factor 7III. Treat/ents 3emophilia is treated by infusing the missing clotting factor. The amount infused depends upon the severity of bleeding, the site of the bleeding, and the si$e of the patient. In the past, mild hemophilia ( was typically treated with infusion of cryoprecipitate or desmopressin acetate ADD(70C, which causes release of factor 7III that, is stored within the body on the lining of blood vessels. Today, e perts recommend desmopressin in*ection or -timate nasal spray.

13

1lotting factors are found in plasma and, to a greater e tent, in plasma concentrates. -ome plasma concentrates are intended for home use and can be self>administered, either on a regular basis to prevent bleeding or at the first sign of bleeding. ;ore often, they are administered three times a day, but both the dose and frequency depend on the severity of the bleeding problem. The dose is ad*usted according to the results of periodic blood tests. During a bleeding episode, more clotting factors are needed. To prevent a bleeding crisis, people with hemophilia and their families can be taught to administer factor 7III concentrates at home at the first signs of bleeding. 0eople with severe forms of the disease may need regular prophylactic infusions, which bring factor levels higher than )B to prevent bleeds. Depending on the severity of the disease, DD(70 or factor 7III concentrate may be given prior to dental e tractions and surgery to prevent bleeding. Immuni$ation with hepatitis B vaccine is necessary because of the increased ris% of e posure to hepatitis due to frequent infusions of blood products. =ene therapy and fetal tissue implant techniques are under study as possible treatments. 0eople who have hemophilia should avoid situations that might cause bleeding. They should be conscientious about dental care so they won't need to have teeth e tracted. 0eople who have hemophilia should also avoid certain drugs that can aggravate bleeding problemsF G (spirin G 3eparin G Warfarin G 1ertain analgesics such as nonsteroidal anti>inflammatory drugs Treatment should be coordinated by a healthcare practitioner who is e pert in the field, such as a hematologist of hemophilia treatment center nurse. The #ational 3emophilia Eoundation's ;edical and -cientific (dvisory 1ouncil A;(-(1C made recommendations for treatment of hemophilia in #ovember of )999.

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They includeF G Eactor 7III products for patients who are 3I7 seronegative, including 'ecombinant factor 7III, especially for young and newly diagnosed patients who have not received seropositive. G 1ryoprecipitate is not recommended because of the ris% of 3I7 and hepatitis infection. Despite greatly improved screening and purification for viral inactivation in blood products, cryoprecipitate can still contain viruses. G ;ild hemophilia ( should be treated with desmopressin, in a DD(70 in*ection or -timate nasal spray. Co/0lications G 1hronic *oint deformities, caused by recurrent bleeding into the *oint, may be managed by an orthopedic specialist G Intracerebral hemorrhage is another possible complication. -ome persons with hemophilia develop antibodies to transfused factor 7III. (s a result, the transfusions are ineffective. If antibodies are detected in blood samples, the dosage of the plasma concentrates may be increased, or different types of clotting factors or drugs to reduce the antibody levels may be used. In the past, the plasma concentrates carried the ris% of transmitting blood>borne diseases such as hepatitis and (ID-. (bout <" percent of persons with hemophilia who were treated with plasma concentrates in the early )9."s were infected with 3I7. 3owever, the ris% of transmitting 3I7 infection through plasma concentrates has been virtually eliminated by today's use of screened and processed blood and a genetically engineered factor 7III A'ecombinantC. any blood or plasma>derived products. G Immunoaffinity purified factor 7III concentrates for patients who are 3I7

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He/o0hilia , AEactor ID DeficiencyC 1hat Is It2 3emophilia is a bleeding disorder caused by a deficiency in one of the blood clotting factors. 3emophilia B Aalso called +1hristmas disease+ after -tephen 1hristmas, a British boy in the !"th century who was first diagnosed with itC is a deficiency in clotting factor ID. 3emophilia ( is seven times more common than hemophilia B. The incidence of hemophilia B is one in /?,@"" men. 3emophilia B is a hereditary disorder in which the clotting ability of the blood is impaired and prolonged bleeding results. -mall wounds and punctures are usually not a problem. But uncontrolled internal bleeding can result in pain, swelling and permanent damage, especially to *oints and muscles. The outcome is good with treatment and management. ;ost people with hemophilia B are able to lead relatively normal lives. Inheritance $attern 3emophilia B is caused by an inherited se >lin%ed recessive trait with the defective gene located on the D chromosome. Eemales are carriers of this trait. Eifty percent of the male offspring of female carriers will have the disease, and @"B of their female offspring will be carriers. (ll female children of a male with hemophilia will be carriers of the trait. 2ne fifth of all cases of hemophilia B occur when there is no family history of the disorder. In these cases, hemophilia develops as the result of a new or spontaneous gene mutation. =enetic counseling may be advised for carriers. Eemale carriers can be identified by testing. A woman is definitely a hemophilia carrier if she is: G the biological daughter of a man with hemophiliaK G the biological mother of more than one son with hemophiliaK G the Biological mother of one son with hemophilia and has at least one other

16

blood relative with hemophilia. A woman may or may not be a hemophilia carrier if she is: G the biological mother of one son with hemophiliaK G the sister of a male with hemophiliaK G an aunt, cousin or niece of an affected male related through maternal tiesK G the biological grandmother of one grandson with hemophilia. y/0to/s and Diagnosis 3emophilia is caused by several different gene abnormalities. The severity of hemophilia B symptoms depends on how a particular gene abnormality affects the activity of factor ID. When the activity is less than )B of normal, episodes of prolonged bleeding may occur for no apparent reason. -everity of symptoms can vary, but severe forms become apparent early on. 0rolonged bleeding is the disease's hallmar% and typically manifests itself when an infant is circumcised. (dditional bleeding manifestations ma%e their appearance when the infant becomes mobile. ;ild cases may go unnoticed until later in life, when they occur in response to surgery or trauma. Internal bleeding may occur anywhere and bleeding into *oints is common. 'is% factors are a family history of bleeding and being male. The incidence of hemophilia B is one in /?,@"" men. -ymptoms includeF G #ose bleeds G Bruising G spontaneous bleeding G bleeding into *oints and associated pain and swelling G =astrointestinal tract and urinary tract hemorrhage G Blood in the urine or stool G prolonged bleeding from cuts, tooth e traction and surgery G prolonged bleeding following circumcision 0eople whose clotting activity is @B of normal may have only mild hemophilia. They rarely have unprovo%ed bleeding episodes, but surgery or in*ury may cause

17

uncontrolled bleeding, which can be fatal. ;ilder hemophilia may not be diagnosed at all, although some people whose clotting activity is )"B to !@B of normal may bleed e cessively after surgery, dental e tractions or a ma*or in*ury. =enerally, the first bleeding episode occurs before ). months of age, often after a minor in*ury. ( child who has hemophilia bruises easily. 8ven an in*ection into a muscle can cause bleeding that results in a large bruise AhematomaC. 1ontinuous bleeding into the *oints and muscles can ultimately lead to crippling deformities. Bleeding can swell the base of the tongue until it bloc%s the airway, ma%ing breathing difficult. ( slight bump on the head can trigger substantial bleeding in the s%ull, causing brain damage and death. ( doctor may suspect hemophilia in a child whose bleeding is unusual. ( laboratory analysis of blood samples can determine whether the child's clotting is abnormally slow. If it is, the doctor can confirm the diagnosis of hemophilia and determine the severity by testing the activity of factor ID. 1oagulation studies involving many tests are performed if the person tested is the first one in the family to have the bleeding disorder. 2nce the defect has been identified, other family members will need less testing to diagnose the disorder. Treat/ents :i%e hemophilia (, hemophilia B is typically treated by infusing the missing clotting factor. The amount infused depends upon the severity of bleeding, the site of the bleeding and the si$e of the patient. ( hepatitis B vaccine is recommended for individuals with hemophilia B because they are at increased ris% of developing hepatitis due to e posure to blood products. 1lotting factors are found in plasma and, to a greater e tent, in plasma concentrates. -ome plasma concentrates are intended for home use and can be self>administered, either on a regular basis to prevent bleeding or at the first sign of bleeding. ;ore often, they are administered three times a wee% Aprophyla isC, but both the dose and frequency depend on the severity of the bleeding problem. The

18

dose is ad*usted according to the results of periodic blood tests. During a bleeding episode, more clotting factors are needed. Treatment should be coordinated by a healthcare practitioner who is an e pert on the disease. To prevent a bleeding crisis, people with hemophilia and their families can be taught to administer factor ID concentrates at home at the first signs of bleeding. 0eople with severe forms of the disease may need regular prophyla is infusions two to three times a wee%. Depending on the severity of the disease, factor ID concentrate may be given prior to dental e tractions and surgery to prevent bleeding. =ene therapy and fetal tissue implant techniques are under study as possible treatments. 0eople who have hemophilia should avoid situations that might provo%e bleeding. They should be conscientious about dental care so they won't need to have teeth e tracted. If people who have milder forms of hemophilia need to have dental or other surgery, the drug desmopressin acetate ADD(70C may be given to improve clotting temporarily so that transfusions can be avoided. 0eople who have hemophilia should also avoid certain drugs that can aggravate bleeding problemsF G aspirin G heparin G warfarin G certain analgesics, such as nonsteroidal antiinflammatory drugs The #ational 3emophilia Eoundation's ;edical and -cientific (dvisory 1ouncil A;(-(1C made recommendations for treatment of hemophilia B in #ovember of )999. They include G 'ecombinant factor ID products for patients who are 3I7 seronegative, especially for young and newly diagnosed patients who have not received any blood or plasma>derived products.

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G Today, plasma>derived factor ID products offer greatly reduced ris% for 3I7 and hepatitis B and 1 transmission, but there is still some ris%. Dry heating, solvent> detergent treatment, vapor treatment and sodium thiocyanate plus ultrafiltration and are all effective purification steps, but there remains a slight possibility of viral transmission. G 0atients who are 3I7>seropositive should also be treated with high purity products such as immunoaffinity purified and recombinant factor 7III products. G Eor patients with inhibitors to factors 7III and ID, there is 'ecombinant Eactor 7IIa A#ovo-evenC. 0roduced by baby hamster %idney cells, no human albumin or other proteins are used in its production, reducing virus ris%. There is also 0orcine factor 7III A3yate 1C and activated prothrombin comple concentrates. Co/0lications G 1hronic *oint deformities, caused by recurrent bleeding into the *oint, may be managed by an orthopedic specialist. G Intracerebral hemorrhage may also occur. G Thrombosis may occur following use of factor ID concentrate. -ome persons with hemophilia develop antibodies to transfused factor ID. (s a result, transfusions become ineffective. If antibodies are detected in blood samples, the dosage of the plasma concentrates may be increased, or different types of clotting factors or drugs to reduce the antibody levels may be used. In the past, plasma concentrates carried the ris% of transmitting blood>borne diseases such as hepatitis and (ID-. (bout <"B of persons with hemophilia who were treated with plasma concentrates in the early )9."s were infected with 3I7. 3owever, the ris% of transmitting 3I7 infection through plasma concentrates has been virtually eliminated by today's use of screened and processed blood.

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%on 1ille&rand Disease 1hat Is It2 7on Willebrand disease is a hereditary deficiency or abnormality of the von Willebrand factor in the blood, a protein that affects platelet function. It's the most common hereditary disorder of platelet function, affecting both women and men. The disease is estimated to occur in )B to !B of the population. The disease was first described by 8ri% von Willebrand, a Einnish physician who reported a new type of bleeding disorder among island people in -weden and Einland. In von Willebrand disease, blood platelets don't stic% to holes in blood vessel walls. 0latelets are tiny particles in the blood that clump together at the site of an in*ury to prepare for the formation of a blood clot. 7on Willebrand factor causes them to bind to areas of a blood vessel that are damaged. If there is too little von Willebrand factor or the factor is defective, platelets do not gather properly when a blood vessel is in*ured. 7on Willebrand factor is found in plasma, platelets and blood vessel walls. When the factor is missing or defective, the first step in plugging a blood vessel in*ury Aplatelets adhere to the vessel wall at the site of the in*uryC doesn't ta%e place. (s a result, bleeding doesn't stop as quic%ly as it should, although it usually stops eventually. There are no racial or ethnic associations with the disorder. ( family history of a bleeding disorder is the primary ris% factor. 'esearchers have identified many variations of the disease, but most fall into the following classifications G Type IF This is the most common and mildest form of von Willebrand disease. :evels of von Willebrand factor are lower than normal, and levels of factor 7III may also be reduced. G Type IIF In these people, the von Willebrand factor itself has an abnormality. Depending on the abnormality, they may be classified as having Type IIa or Type IIb. In Type IIa, the level of von Willebrand factor is reduced, as is the ability of

21

platelets to clump together. In Type IIb, although the factor itself is defective, the ability of platelets to clump together is actually increased. G Type IIIF This is severe von Willebrand disease. These people may have a total absence of von Willebrand factor, and factor 7III levels are often less than )"B. G 0seudo Aor platelet>typeC von Willebrand diseaseF This disorder resembles Type IIb von Willebrand disease, but the defects appear to be in the platelets, rather than the von Willebrand factor. 2nce in a while, people develop what appears to be von Willebrand disease later in life. When this occurs in those who have no family history of the disease, it is thought that they're probably producing antibodies that destroy or decrease the amount of von Willebrand factor. -ome other people have +acquired+ a form of the disease in association with another disorder, such as rheumatoid arthritis, systemic lupus erythematosus, %idney disease and certain cancers. The life span of patients is usually normal length. -ince the disease is genetically transmitted, genetic counseling may be recommended for parents. 7on Willebrand disease can be more complicated for women because of obstetric and gynecological issues. Inheritance $attern :i%e hemophilia, the disease is passed down through the genes. But unli%e hemophilia, which usually affects only males, von Willebrand disease occurs in men and women equally. ( man or woman with the disease has a @"B chance of passing the gene on to his or her child. Types I and II are usually inherited in what is %nown as a +dominant+ pattern. This means that if even one parent has the gene and passes it to a child, the child gets the disease. Whether the child has no symptoms, mild symptoms or, less commonly, severe symptoms, he or she definitely has the disease. 'egardless of severity of the symptoms, the child can still pass the gene to his or her own offspring.

22

Type III von Willebrand disease, however, is usually inherited in a +recessive+ pattern. This type occurs when the child inherits the gene from both parents. 8ven if both parents have mild or asymptomatic disease, their children are li%ely to be severely affected. These patterns of inheritance differ from hemophilia, which is caused by a defect in one of the +se >lin%ed+ chromosomes. ( man with hemophilia cannot pass the gene on to a son, because the abnormality is carried on the D chromosome and a man contributes only a L chromosome to his male offspring. von Willebrand disease is found on the autosomal chromosomes and therefore can be inherited by either males or females. von Willebrand disease can often be traced through several generations in a family. -ome have symptoms while others *ust carry the gene. y/0to/s and Diagnosis Diagnosis can be difficult. When a healthcare practitioner hears of recurrent nosebleeds, easy bruising, heavy menstrual periods or longer than usual bleeding after such routine operations as tonsillectomies or tooth e tractions, diagnostic tests should be performed to rule out the possibility of von Willebrand disease. ,sually, a person with von Willebrand disease has a parent with a history of bleeding problems. Typically, a child bruises easily or has bleeds e cessively after a s%in cut, tooth e traction, tonsillectomy or other surgery. ( woman may have increased menstrual bleeding. Bleeding may worsen at times. 2n the other hand, hormonal changes, stress, pregnancy, inflammation and infections may stimulate the body to increase production of the von Willebrand factor and temporarily improve clot formation. :aboratory tests may determine that the number of platelets is normal but bleeding time is abnormally long. Bleeding time is the amount of time that elapses before bleeding stops after a small cut is made on the forearm. To ma%e the diagnosis,

23

doctors may order tests that measure the amount of von Willebrand factor in the blood. Because the von Willebrand factor is the protein that carries factor 7III in the blood, the blood level of factor 7III may also be decreased. Diagnostic signs can includeF G normal platelet count G prolonged bleeding time G reduced von Willebrand factor level G reduced platelet adhesion may occur G reduced or increased platelet aggregation Aplatelet aggregation testC G ristocetin cofactor is reduced Treat/ents There are a range of treatment choices that depend on whether the illness is mild or severe. ;any people with von Willebrand disease never even need treatment. -timate, desmopressin acetate ADD(70C, a drug sprayed into the nose, is the treatment of choice for mild von Willebrand disease. Bleeding is usually controlled in individuals with mild von Willebrand disease by using this nasal spray to boost their own factor 7III and von Willebrand levels. DD(70 may be given to increase the amount of the von Willebrand factor long enough for surgery or dental procedures to be performed. DD(70 is a synthetic product that carries no ris% of infectious disease. Eor e cessive bleeding, infusions of a viral inactivated factor 7III product rich in von Willebrand factor, such as 3umate>0, (lphanate and Ioate D7I, may be required. If trauma occurs or surgery is scheduled, desmopressin acetate can be given to raise the levels of von Willebrand factor, which will decrease the tendency toward bleeding. Eresh plasma may also be used to decrease bleeding but the ris% of viral infection can be high. 1hildren with von Willebrand disease should avoid unnecessary trauma, and those with severe disease should avoid certain contact sports. During menstruation,

24

adolescent females may want to ta%e e tra precautions to avoid accidents. During bleeding episodes, they can elevate and apply cold compresses and gentle pressure to the area. During nosebleeds, they can apply pressure over the bridge of the nose lean forward to prevent blood running down the bac% of the throat and being swallowed. (spirin and many of the drugs used for arthritis can aggravate bleeding because they interfere with platelet function. 0eople who have von Willebrand disease can ta%e acetaminophen for pain relief because it doesn't inhibit platelet function. The #ational 3emophilia Eoundation's ;edical and -cientific (dvisory 1ouncil A;(-(1C made recommendations for treatment of von Willebrand disease in #ovember of )999. They includeF G -timate, desmopressin acetate ADD(70C, a nasal spray or in*ection. G Eor patients who have become unresponsive to DD(70 or need surgical procedures, viral>inactivated factor 7III preparations rich in von Willebrand factor, such as (lphanate, 3umate>0 and Ioate D7I, are recommended. G 1ryoprecipitate is not recommended e cept in life>threatening emergencies because of the ris% of 3I7 and hepatitis infection. Despite greatly improved screening and purification for viral inactivation in blood products, cryoprecipitate can still be infectious. Co/0lications (fter any %ind of surgery, hemorrhaging may occur. The condition is worsened by the use of aspirin and other nonsteroidal anti>inflammatory drugs. Women may have heavy menstrual periods as well as ris%s during pregnancy and childbirth. . Those who have this disorder and are scheduled for surgery or are in an accident, should be sure to notify healthcare providers about the condition. Factor I Deficiency A(fibrinogenemiaC 1hat Is It2

25

Eibrinogen, also %nown as factor I, is needed for most types of platelet aggregation. It's the last step in the clotting processMthe +glue+ that holds the clot together. 0eople who have a factor I deficiency have a combined bleeding and clotting disorder, meaning that both platelets and clotting are abnormal. -ince its discovery in )9!", there have only been about !"" cases of this disorder. Included under factor I deficiency are several rare coagulation disorders %nown as congenital fibrinogen defects. They includeF G afibrinogenemia G hypofibrinogenemia G dysfibrinogenemia The first two are called quantitative abnormalities because they have to do with an absent or low quantity of fibrinogen. The third is called a qualitative abnormality because the fibrinogen does not wor% well. (fibrinogenemia is the complete absence of fibrinogen. 3ypofibrinogenemia is a low level of fibrinogenMless than )""mg in )d: of blood. Both conditions are inherited in an autosomal fashion and can affect males and females. The severity of the disorder is related to the amount of fibrinogen. (fibrinogenemia is usually discovered in newborns and can cause bleeding from the umbilical cord, genitourinary tract or central nervous system. 0eople with hypofibrinogenemia may have little, moderate or severe bleeding. Dysfibrinogenemias are due to variations in the factor I molecule. ;ore than 4" different types of dysfibrinogenemia have been identified. Inheritance $attern The disorder is not se >lin%ed as is hemophilia. It affects both males and females with equal frequency. It is autosomal recessive, which means that if the clotting defect is inherited from a parent, the child will be a genetic carrier of the condition, but may or may not have symptoms.

26

y/0to/s and Diagnosis Eew people who have any of these disorders suffer symptoms, although some are predisposed to form blood clots AthrombosisC. Treat/ents ;any people with hypofibrinogenemia or dysfibrinogenemia need no treatment. Those who require treatment may be given cryoprecipitate or fresh fro$en plasma. (nticoagulants are sometimes prescribed to reduce the ris% of thrombosis. The goal of treatment is to raise the patient's fibrinogen level to )"" mgHd: for minor bleeding and up to !"" mgHd: for surgery or severe bleeding. A2ne unit of fresh fro$en plasma has about ?@" mg of fibrinogen.C Co/0lications 0lasma levels of fibrinogen e ceeding ),""" mgHd: have been reported to possibly increase the ris% of thrombosis. In women, menstrual bleeding can be a severe problem and must be controlled Factor II Deficiency A0rothrombinC 1hat Is It2 0rothrombin is a vitamin I>dependent proen$yme that functions in coagulation. There are two types of this deficiency, a congenital version called hypoprothrombinemia, and an acquired version called dyspothrombinemia. ( life>long bleeding disorder when congenital, factor II deficiency is e tremely rare. In fact, only /" cases of this hereditary clotting factor defect have been identified in the whole world. (cquired factor II deficiency is more common. It results from vitamin I deficiency, severe liver disease and therapeutic use of anticoagulant drugs. 'is% factors for vitamin I deficiency are prolonged use of antibiotics, bile duct obstruction and intestinal malabsorption Ainadequate absorption of nutrients from the intestinal tractC disorders. -ome newborns are born with vitamin I deficiency

27

If the deficiency is caused by liver disease, the outcome depends on control of the liver problem. 7itamin I administration will correct vitamin I deficiency. 8ither form may lead to severe bruising, e cessive menstrual bleeding, postoperative hemorrhage or occasional muscle bleeds. Inheritance $attern ( congenital factor II deficiency is a very rare inherited disorder that results in deficient blood clotting. The disorder is not se >lin%ed as is hemophilia. It affects both males and females with equal frequency. It is autosomal recessive, which means that if the clotting defect is inherited from a parent, the child will be a genetic carrier of the condition, but may or may not have symptoms. ( family history of bleeding disorder is a ris% factor. y/0to/s and Diagnosis -igns and symptoms vary with the level of prothrombin. 0atients with levels greater than @"B of normal have no bleeding problems, whereas people with levels from !B to @"B may easily bruise or suffer from epista is, menorrhagia, muscle hemorrhages, postpartum hemorrhages and hemorrhage following surgery and trauma. -ymptoms includeF G umbilical cord bleeding at birth G nose bleeds G abnormal menstrual bleeding G abnormal bleeding after delivery G bleeding after trauma G bleeding after surgery G easy bruising -igns and TestsF G prolonged prothrombin time G prolonged partial thromboplastin time G factor II assay showing decreased activity G levels of prothrombin ranging from !B to @"B of normal

28

Treat/ents Treatment depends on the severity of the disorder and the type of bleeding. ;ild cases may be treated with plasma infusion. :oss of blood can be controlled by infusions of fresh fro$en plasma. -evere factor II deficiencies may be treated with prothrombin comple concentrates A011sC. When necessary, it can be treated with plasma replacement therapy. 8ffective control of a hemorrhage is achieved when prothrombin levels are at /"B to @"B of normal. =enetic counseling may be helpful in the case of congenital disorders. The use of vitamin I in malabsorption and long>term antibiotic use may be preventative. If the disorder is caused by vitamin I deficiency, then vitamin I is prescribed. Diagnosis of a bleeding disorder is important so that precautionary measures can be ta%en if surgery is needed or anticipated. The #ational 3emophilia Eoundation's ;edical and -cientific (dvisory 1ouncil A;(-(1C made recommendations for treatment of factor II deficiency in #ovember of )999. They includeF G 0rothrombin comple concentrates A011sC can be used, but these products vary considerably in the amount of factors they contain. G Eresh fro$en plasma can be used as along as it is processed to reduce the ris% of viral infection. Co/0lications Bleeding has to be controlled in instances of trauma or surgery, or else bleeding into the brain or s%ull can occur. Factor % Deficiency A0arahemophilia, :abile factor or 0roaccelerin DeficiencyC 1hat Is It2 Eactor 7 deficiency is also %nown as 2wren's disease or parahemophilia. This deficit was identified in #orway in )9?/. -ince then about )@" cases have been

29

reported, occurring in both men and women. The e act frequency of this rare disorder is un%nown, but is estimated to be one per ) million. The role of factor 7 is to accelerate the activity of thrombin. When levels of factor 7 are low, blood clotting is delayed or it progresses slowly. 0eople with this deficiency may have occasional nosebleeds, e cessive menstrual bleeding and bruisingK although, many have no symptoms. The first sign of this condition may be bleeding following surgery. In this disorder, bleeding ranges from mild to severe. The disease is similar to hemophilia, e cept that bleeding into *oints is uncommon. Bleeding can occur almost anywhere in the body, and death from hemorrhage has occurred with this disorder. 8 cessive bleeding with menstrual periods and postpartum hemorrhage occurs frequently. ( family history of a bleeding disorder is a ris% factor. ;en and women are affected equally. The probable outcome is good with proper diagnosis and treatment. Inheritance $attern The disorder is not se >lin%ed as is hemophilia. It affects both males and females with equal frequency. It is autosomal recessive, which means that if the clotting defect is inherited from a parent, the child will be a genetic carrier of the condition, but may or may not have symptoms. -everal families with combined deficiencies of factors 7 and 7III have been reported. y/0to/s and Diagnosis -ymptoms includeF G bleeding into the s%in G e cessive bruising with minor in*uries G nose bleeds G bleeding of the gums G e cessive menstrual bleeding

30

G prolonged or e cessive loss of blood with surgery or trauma Diagnosing the deficiency involves tests and signs such asF G factor 7 assay showing decreased activity G slightly prolonged bleeding time Ain some peopleC G prolonged partial thromboplastin time G prolonged prothrombin time Treat/ents There are no commercially available concentrates of factor 7, so fresh plasma or fresh fro$en plasma infusions are used to correct the deficiency temporarily and should be given daily during a bleeding episode. 2ther plasma is not given because factor 7 deteriorates very rapidly. The half>life of factor 7 is !? hours. This is an inherited disorderK there is no %nown prevention. Co/0lications Dangerous hemorrhaging can occur if bleeding isn't controlled quic%ly. If platelets are used as a source of factor 7, antiplatelet antibodies can be induced. Factor %II Deficiency A0roconvertin or -table EactorC 1hat Is It2 This e tremely rare disorder can be inherited or acquired by people who do not have hemophilia who ta%e 1oumadin, a drug used to inhibit blood clotting. With this disorder, bleeding can vary from mild to severe within the same person over time. Bleeding doesn't always correspond with the severity of the deficiency shown in blood tests. ( history of bleeding may occur in infancy or childhood. =astrointestinal and central nervous system bleeding can also occur. This disorder occurs in one in @"",""" males and females. 1ongenital factor 7II deficiency should be distinguished from acquired factor 7II deficiency, which may result from liver disease, vitamin I deficiency or other malabsorption conditions.

31

When levels of the factor are less than )B of normal, bleeding can be severe. The trauma of birth may cause bleeding in the head of a newborn. 1ircumcision may cause prolonged bleeding. 1hildren and adults may suffer bleeding from nose, gums or gastrointestinal tract, and women may suffer e cessive menstrual bleeding. The probable outcome is good with proper treatment. Inheritance $attern The disorder is not se >lin%ed as is hemophilia. It affects both males and females with equal frequency. It is also autosomal recessive, which means that if the clotting defect is inherited from a parent, the child will be a genetic carrier of the condition, but may or may not have symptoms. Those who have inherited a defective factor 7II gene from only one parent will usually have only moderate levels of the factor but no symptoms. y/0to/s and Diagnosis -everity of bleeding episodes depends on the degree of the severity of the defect. -ymptoms includeF G bleeding of mucous membranes G spontaneous nosebleeds G e cessive bruising G prolonged menstrual bleeding G bleeding into muscles G bleeding into *oints Diagnosis is made by testing for factor 7II in the blood. -igns and tests includeF G prolonged prothrombin time G normal partial thromboplastin time G decreased factor 7II assay

32

Treat/ents Bleeding episodes can be controlled with normal plasma or concentrates containing factor 7II. -evere bleeding may be treated with fresh fro$en plasma or 0rothrombin comple concentrates A011sC. Because the life span of infused factor 7II is very short Atwo to four hoursC, patients may require treatment every two to si hours for severe bleeding or surgery. ;enstrual bleeding can be controlled by the use of oral contraceptives. #ote that factor 7II concentrate is sold only in 8urope, but is available in the ,- on a compassionate basis from the manufacturer AImmuno (gC. The #ational 3emophilia Eoundation's ;edical and -cientific (dvisory 1ouncil A;(-(1C made recommendations for treatment of Eactor 7II deficiency in #ovember of )999. They includeF G 'ecombinant factor 7IIa A#ovo-evenC, which was recently licensed in the ,- and is produced by baby hamster %idney cells. #o human albumin is used. G 0rothrombin comple concentrates A011sC can be used, but these products vary considerably in the amount of factors they contain. G Eresh fro$en plasma can be used as along as it is processed to reduce the ris% of viral infection. Co/0lications These can include hemorrhages, stro%es or other neurological problems related to central nervous system bleeding. Eatal intracranial bleeding caused by birth trauma has occurred. ;enstrual bleeding may also be severe. THROMBOCYTOPENIA Definition Thrombocytopenia is any disorder in which there are not enough platelets. 0latelets are cells in the blood that help blood to clot. This condition is sometimes associated with abnormal bleeding.

33

Causes4 incidence4 and ris5 factors Thrombocytopenia is often divided into three ma*or causes of low plateletsF ). :ow production of platelets in the bone marrow !. Increased brea%down of platelets in the bloodstream Acalled intravascularC /. Increased brea%down of platelets in the spleen or liver Acalled e travascular C Disorders that involve low production in the bone marrow include :

(plastic anemia 1ancer in the bone marrow Infections in the bone marrow ArareC Drugs Avery rareC

Disorders t !t in"o#"e t e $re!%do&n of '#!te#ets inc#ude:

Immune thrombocytopenic purpura (ITP) Drug-induced immune thrombocytopenia Drug-induced nonimmune thrombocytopenia Thrombotic thrombocytopenic purpura Primary thrombocythemia Disseminated intravascular coagulation (DI ) !ypersplenism (an enlarged spleen)

S()'to)s

Bruising #osebleeds or bleeding in the mouth 'ash Apinpoint red spotsC

Other symptoms may be present as well, depending on the a!se o" the ondition# $ild thrombo ytopenia an o !r witho!t symptoms# 34

Si*ns !nd tests

1B1 shows low platelets Bone marrow aspiration or biopsy may be normal or may show low mega%aryocytes Aplatelet precursorsC or an infiltrating disease. 0TT clotting study is normal 0T clotting study is normal 0latelet associated antibodies may be present

Tre!t)ent Treatment depends on the cause of the condition. In some cases, a transfusion of platelets may be required to stop or prevent bleeding. E+'ect!tions ,'ro*nosisThe outcome depends on the disorder causing the low platelet counts # Co)'#ic!tions

3emorrhage =astrointestinal bleeding Avomiting blood or blood in the stoolsC Bleeding in the brain Aintracranial hemorrhageC

C!##in* (our e!#t c!re 'ro"ider %all yo!r health are pro&ider i" yo! e'perien e !ne'plained bleeding or br!ising# Pre"ention (re&ention depends on the spe i"i a!se#

35

DISSEMINATED INTRA.ASC/LAR COAG/LATION DI1 is a syndrome arising as a complication of many different serious and life> threatening illnesses. In its acute AovertC form it is a hemorrhagic disorder, characteri$ed by multiple ecchymoses, mucosal bleeding, and depletion of platelets and clotting factors in the blood. 1hronic AnonovertC DI1, on the other hand, is more subtle and involves thromboembolism accompanied by evidence of activation of the coagulation system. With chronic DI1, coagulation factors may be normal, increased, or moderately decreased, as may the platelet counts. -uccessful management of acute DI1 depends almost entirely on prompt, effective control of the underlying disease. 1hronic DI1 usually can be treated with heparin or low>molecular>weight heparin, but warfarin is sometimes ineffective for long>term control. -uccessful treatment of the underlying disease is necessary to eliminate DI1, whether it is acute or chronic. $athogenesis of DIC DI1 occurs when monocytes and endothelial cells are activated or in*ured by to ic substances elaborated in the course of certain diseases. The response of monocytes and endothelial cells to in*ury is to generate tissue factor on the cell surface, activating the coagulation cascade Afigure )C. In acute DI1, an e plosive generation of thrombin depletes clotting factors and platelets and activates the fibrinolytic system. Bleeding into the subcutaneous tissues, s%in, and mucous membranes occurs, along with occlusion of blood vessels caused by fibrin in the microcirculation.

36

In chronic DI1, the process is the same, but it is less e plosive. ,sually there is time for compensatory responses to ta%e place, which diminish the li%elihood of bleeding but give rise to a hypercoagulable state. These changes in the blood can be detected by testing the coagulation system.)>? Thromboembolism occurs in this setting, and when oral anticoagulants are given following heparin therapy, there is a tendency for it to recur. :ong>term therapy with low>molecular>weight heparin may be a solution to this problem until the underlying cause can be brought under control.

37

Conditions associated 6ith DIC The conditions that regularly give rise to the DI1 syndrome are outlined in table ) A),@>.C. Inowledge of this association is helpful to the physician, who may then anticipate onset and intervene in a timely manner. Ta&le 1. Conditions underlying DIC syndro/e Infections (cute DI1F Bacteria and their to ins, fungi, viruses, ric%ettsiae 1hronic DI1F (ny chronic infection Aeg, tuberculosis, abscesses, osteomyelitisC Noninfectious infla//atory diseases Inflammatory bowel diseaseF 1rohn's disease and similar disorders O&stetrical co/0lications (cute DI1F (bruptio placentae, abortions Aespecially therapeutic abortionsC, amniotic fluid embolism, hemorrhagic shoc% 1hronic DI1F Dead fetus syndrome +alignancy (cute DI1F (cute promyelocytic leu%emia, acute myelomonocytic or monocytic leu%emia, disseminated prostatic carcinoma 1hronic DI1F :ung, breast, gastrointestinal malignancy %ascular disease (cute DI1F Brain infarction or hemorrhage 1hronic DI1F (ortic aneurysm, giant hemangioma %eno/s (cute DI1F -na%e, spider ArareC

Trau/a K

38

(cute DI1F ;assive tissue destruction, brain damage Others (cute DI1F 3eparin>induced thrombocytopenia with thrombosis A3ITTC, purpura fulminans in newborns Ahomo$ygous protein 1 deficiencyC$DI1, disseminated intravascular coagulation.

It is well %nown that Trousseau described an association between cancer and venous thromboembolism. 3owever, it is less well %nown that half of his patients did not have cancer but rather had tuberculosis A9C. 2ther inflammatory diseases are also often associated with thromboembolism. 0atients with these conditions have the hypercoagulable state %nown as chronic DI1. #onbacterial thrombotic endocarditis syndrome.+ Diagnosis of DIC Diagnostic findings in DI1 are outlined in table !. The clinical and laboratory features of acute DI1 differ from those of chronic DI1. This is only a general rule, however, in that chronic DI1 in dead fetus syndrome and in certain vascular disorders Aeg, aortic aneurysmC may show coagulation abnormalities similar to those found in acute DI1 A)",))C. Ta&le ". Clinical and la&oratory findings in DIC Acute DIC 1linical findings

and

arterial

thromboembolism

constitute

+arterial

Trousseau's

;ultiple bleeding sites 8cchymoses of s%in, mucous membranes 7isceral hemorrhage Ischemic tissue

39

:aboratory abnormalities

1oagulation abnormalitiesF prolonged prothrombin time, activated partial thromboplastin time, thrombin timeK decreased fibrinogen levelsK increased levels of ED0 Aeg, on testing for ED0, D dimerC

0latelet count decreased as a rule but may be falling from a higher level yet still be normal -chistocytes on peripheral smear

Chronic DIC 1linical findings

-igns of deep venous or arterial thrombosis or embolism -uperficial venous thrombosis, especially without varicose veins ;ultiple thrombotic sites at the same time -erial thrombotic episodes

:aboratory abnormalities

;odestly increased prothrombin time in some patients -hortened or lengthened partial thromboplastin time #ormal thrombin time in most patients 3igh, normal, or low fibrinogen level 3igh, normal, or low platelet count Increased levels of ED0 Aeg, on testing for ED0, D dimerC 8vidence of molecular mar%ersN Aeg, thrombin>antithrombin comple es, activation mar%ers on platelet membranes, prothrombin fragment E)J!C

DI1, disseminated intravascular coagulationK ED0, fibrin>fibrinogen degradation products.

40

NThese tests are used primarily in research.

Diagnosis of acute DI1 can be established without performing all of the laboratory tests we %now to have abnormal findings in most cases of this syndrome. This is especially true when the clinical setting is consistent with DI1 and results of routine tests Aeg, platelet count, prothrombin time, partial thromboplastin time, fibrinogen levelC are all abnormal Atable !C. Disorders such as hepatic insufficiency, hepatic necrosis, anticoagulant overdose, and the presence of certain circulating anticoagulants should also be considered in the differential diagnosis, particularly when there is no obvious underlying disease to account for DI1 A)">)/C. ( number of other laboratory mar%ers are associated with DI1, including prolonged thrombin time and decreased levels of antithrombin III, protein 1, plasminogen, and alpha!>antiplasmin. 3owever, these same abnomalities may be seen in severe liver disease and in severe hemorrhage caused by plasma loss. The one coagulation system test that helps distinguish between DI1 and liver disease is D dimer. This test is usually negative in liver disease unless there is massive necrosis, which can cause DI1. (nother laboratory clue to chronic DI1 is a shortened activated partial thromboplastin time A)?,)@C. 0latelet counts may be normal, high, or moderately low. In addition, platelet counts may rise with heparin therapy and fall when heparin is stopped in the presence of a hypercoagulable state or chronic DI1.

+anage/ent of DIC Treatment of the underlying disease is the mainstay of management of either acute or chronic DI1 Atable /C. (dditionally, acute DI1 is treated with blood products that

41

control bleeding if necessary. 8 perimental drugs Aeg, concentrate of the tissue factor pathway inhibitors antithrombin III, protein 1, or thrombomodulinC are currently undergoing clinical trials A@,)<C. Ta&le -. Treat/ent o0tions for DIC syndro/e Treat the underlying disease (void delay Treat vigorously Aeg, shoc%, sepsis, obstetrical problemsC +anage the DIC (cute DI1 Without bleeding or evidence of ischemia #o treatment With bleeding Blood components as needed Eresh fro$en plasma 1ryoprecipitate 0latelet transfusions With ischemia (nticoagulants Asee +with thromboembolism+ belowC after bleeding ris% is corrected with blood products 1hronic DI1 Without thromboembolism #o specific therapy needed but prophylactic drugs Aeg, low>dose heparin, low>molecular>weight heparinC may be used for patients at high ris% of thrombosis With thromboembolism 3eparin or low>molecular>weight heparin, trial of warfarin sodium A1oumadinC. AIf warfarin is unsuccessful, long>term use of low>molecular>weight heparin may be helpful.CN

42

DI1, disseminated intravascular coagulation. N-ome patients respond to warfarin, others do not. ,se of low>molecular>weight heparin for prolonged periods has potential ha$ards and is e pensive but can be useful when warfarin therapy fails despite good control Ainternational normali$ed ratio OI#'P, !>/C.

When there is no serious hemorrhage or unusual ris% of bleeding or thromboembolism in acute DI1, it is appropriate to observe rather than treat. (s ;ilton stated in "n !is #lindness$ +They also serve who only stand and wait.+ 1hronic DI1 is primarily a hypercoagulable state that may result in venous or arterial thrombosis. In some vascular and obstetrical disorders, chronic DI1 manifests primarily by consumption coagulopathy of mild to modest degree. -tandard treatment of thromboembolism with heparin or low>molecular>weight heparin is appropriate, although it is important to be aware of warfarin resistance. -hould thrombosis recur while a patient is receiving warfarin, it is advisable to use heparin or low>molecular>weight heparin until the underlying disease is fully controlled or cured. IDIO$ATHIC THRO+,OC)TO$*NIC $UR$URA 1hat is IT$2 IT0 stands for idiopathic thrombocytopenic purpura. +Idiopathic+ means that the cause is un%nown. +Thrombocytopenic+ means the blood doesn't have enough platelets. +0urpura+ means a person has e cessive bruising. Lou may also hear IT0 called +immune thrombocytopenic purpura.+ In people with IT0, all of the blood cells are normal e cept for the blood platelets. 0latelets are the tiny cells that seal minor cuts and wounds and form blood clots. ( person with too few platelets bruises easily and bleeds for a long time after being

43

in*ured. Tiny red dots on the s%in, called petechiae Asay +pe>T88I>ee>ay+C might also appear. When the platelet count is very low, the person with IT0 might have nosebleeds that are hard to stop, or might have bleeding in the intestines. 1hat causes IT$2 The cause of IT0 is not %nown. 0eople with IT0 form antibodies that destroy their blood platelets. #ormally, antibodies are a healthy response to bacteria or viruses. In people with IT0, however, the antibodies attac% the body's own blood platelets. 1ho gets IT$2 There are ! types of IT0. 2ne type affects children, and the other type affects adults. In children, the usual age for getting IT0 is ! to ? years of age. ;ost adults with IT0 are young women, but it can occur in anyone. IT0 does not run in families. Ho6 does IT$ affect children2 IT0 is different in children than in adults. ;ost children with IT0 have a very low platelet count that causes sudden bleeding. The usual symptoms are bruises and the tiny red dots on the s%in. #osebleeds and bleeding gums are also common. Ho6 is IT$ diagnosed2 Lour doctor can diagnose IT0 by as%ing questions about your health and doing a physical e am. Lour doctor may ta%e a blood sample and loo% at it under a microscope. Ho6 is IT$ treated in children2 Because most children recover with no treatment, many doctors recommend *ust watching them carefully and ta%ing care of the bleeding symptoms. 1hildren don't have to go to the hospital if good care is available at home. 3owever, some doctors recommend a short treatment with prednisone pills or intravenous infusions Agiven

44

in a veinC of gamma globulin to increase the platelet count more quic%ly. Both medicines have some side effects. Ho6 does IT$ affect adults2 In most adults, IT0 lasts much longer than it does in children. (t the time of diagnosis, most adults have noticed increased bleeding and easy bruising for several wee%s, or even months. In women, increased menstrual blood flow is a ma*or sign. ;any adults have only mild thrombocytopenia. In fact, quite a few people have no bleeding symptoms. They are only diagnosed with IT0 when their blood is chec%ed for another reason and a low blood platelet count is found. Ho6 is IT$ treated in adults2 Treatment of IT0 in adults is aimed at increasing the blood platelet count. This is not the same as curing the disease. 0atients may ta%e prednisone for several wee%s, even a month or longer. 3owever, when the medicine is stopped, the platelet counts may get low again. If prednisone doesn't help enough, the spleen can be removed. The spleen ma%es most of the antibodies that destroy the blood platelets. It also destroys old or damaged blood cells. In an otherwise healthy young person, removal of the spleen is not a serious operation. 1hat a&out IT$ in 0regnant 6o/en2 Diagnosing IT0 during pregnancy can be difficult, because platelet counts may be low for other reasons. (bout @B of women have mildly low platelet counts at the end of a normal pregnancy. The cause of this is un%nown. The platelet count goes bac% to normal right after delivery.

45

( baby born to a mother with IT0 may have a low blood platelet count a few days to a few wee%s after birth. These babies are usually %ept in the hospital for several days for observation Awatching to ma%e sure they are o%C before they go can home. Thro/&otic thro/&ocyto0enic 0ur0ura

1hat is thro/&otic thro/&ocyto0enic 0ur0ura2

Thrombotic thrombocytopenic purpura ATT0C is a rare blood condition characterised by the formation of small clots AthrombiC within the circulation, which results in the consumption of platelets and thus a low platelet count AthrombocytopeniaC. 1hat causes TT$2 ,ntil recently the cause of TT0 remained elusive. 3owever, recent research points to the involvement of a protein in the plasma called von Willebrand factor AvWEC. DRU'7INDUC*D I++UN* THRO+,OC)TO$*NIA D',=>I#D,18D I;;,#8 T3'2;B21LT208#I( is a condition where the use of certain drugs leads to the formation of antibodies against platelets. These antibodies can cause a low platelet count, which ma%e bleeding more li%ely. If these antibodies are formed during pregnancy, they may pass from the mother to the fetus.

Thro/&ocyto0enia

8noni//une#

drug7induced9

Noni//une

thro/&ocyto0enia 7 drug7induced Drug>induced nonimmune thrombocytopenia is a reduction in normally functioning platelets that can be caused by certain drugs.

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0latelets are important in forming blood clots. 1ertain drugs may decrease the number of platelets by damaging the bone marrow where platelets are made. Decreased platelets may cause easy bruising or abnormal bleeding. Bleeding can be life>threatening if it occurs in the brain or other vital organ. 2ther drugs can increase the ris% of bleeding by preventing platelets from wor%ing normally. ( common e ample of this is aspirin $RI+AR) THRO+,OC)TH*+IA 8ssential thrombocythemiaK 8ssential thrombocytosis 0rimary thrombocythemia is a condition of overproduction of platelets without a recogni$able cause. Causes4 incidence4 and ris5 factors 0rimary thrombocythemia is a slowly progressing disorder caused by overgrowth of a type of cell that is a precursor of blood cells. (lthough the platelets are primarily affected, the red blood cells and white blood cells are also involved. The disease has similarities to polycythemia vera, chronic myelogenous leu%emia, and myelofibrosis. ,sually it affects people in middle age. Bleeding can occur from the gastrointestinal tract, respiratory system, urinary tract, or s%in. The formation of blood clots, called thrombosis, may coincide with bleeding episodes. It may even cause stro%es in some people. 'is% factors are un%nown. The incidence is about / out of )"",""" people. y/0to/s

#osebleeds Aepista is C Bleeding from the gums Bleeding from the gastrointestinal tract

47

8asy bruising 0rolonged bleeding from surgical procedures or tooth e traction 8nlarged lymph nodes ArareC Bloody stools 3eadache #umbness of hands or feet Di$$iness ,lcers on fingers or toes

igns and tests Bone marrow aspiration.

1B1 that shows elevated platelet count. ,ric acid level may be elevated. 0hysical e amination may show enlarged spleen or liver.

Treat/ent If a patient is having life>threatening complications, rapid decrease of the platelet count may be achieved through platelet pheresis, a procedure to remove platelets from the blood directly. :ong>term decrease of the platelet count using medications can reduce both bleeding and clotting complications. ;ost common medications include hydro yurea, interferon>alpha, or anagrelide. Eor patients with a %nown clotting tendency, aspirin may help decrease clotting episodes. -ome patients do not need any treatment.

*x0ectations 80rognosis#

48

The outcome varies with reports ranging from prolonged periods without complications in some people, to fatalities from complications related to hemorrhage and thrombosis in others. Co/0lications

-evere hemorrhage Thrombotic episodes Astro%e, heart attac%, or blood clots in e tremitiesC (cute leu%emia or myelofibrosis can develop in some patients

Calling your health care 0ro:ider

If une plained or prolonged bleeding occurs. If chest pain, leg pain, confusion, wea%ness, numbness, or other new symptoms develop

H)$*R $(*NI + 3ypersplenism is increased activity of the spleen caused by tumors, anemia, malaria, tuberculosis, and various connective tissue and inflammatory diseases. (n enlarged spleen is often accompanied by a low level of one or more types of blood cells. The enlarged spleen can cause stomach pain on the left side, as well as feeling full prematurely after eating D8#T(: 87(:,(TI2# good thorough medical history a physical e amination screening clinical lab tests e cessive bleeding following surgical procedure

49

good thorough history Eamily 3D 0ersonal 3D ;edications 0ast Q 0resent Illness -pontaneous Bleeding

'87I8W 0(TI8#TR- ;8DFIVE DRUGS T3(T I#T8'E8'8 WIT3 38;2-T(-I (-0I'I# (#TI12(=,:(#T(#TIBI2TI1(:1232: (#TI1(#18'

2'(: ;(#IE8-T(TI2# 0etechiae Q 8cchymosis =ingival 3yperplasia -pontaneous =ingival Bleeding ,lceration of 2ral ;ucosa :ymphadenopathy

50

D8#T(: 0(TI8#T :2W 'I-I 0atients with #o 3 of Bleeding Disorders #ormal :aboratory 'esults

;2D8'(T8 'I-I 0atients on 1hronic 2ral (nticoagulant Therapy. 0T is ).@ > ! Times 1ontrol 'ange 0atients on 1hronic (spirin Therapy

D8#T(: 0(TI8#T 3I=3 'I-I 0atients with Inown Bleeding Disorders 0atients without Inown Bleeding Disorders Who 3ave (bnormal :aboratory 'esults D8#T(: ;(#(=8;8#T :2W 'I-I 0(TI8#T #ormal 0rotocol

;2D8'(T8 'I-I 0(TI8#T (nticoagulants > 1onsult 0hysician (spirin Therapy > BT, 1onsult 0hysician

3I=3 'I-I 0(TI8#T51

1lose 1oordination with 0hysician 3ospitali$ation A0latelet TransfusionC TherapyCADialysisC AEactor 'eplacementCA7it I

CONC(U ION The history Amedical Hfamily historyC is e tremely important in evaluating patients with disorders of hemostasis.The duration of the bleeding disorder must be determined, since many of these disorders are inherited. 1areful questioning may be necessary to reveal a life long history of bleeding and bruising a family history of bleeding may be elicited with a carefully ta%en history. Dental e tractions are a very common ma*or stresses of the haemostatic mechanism, and a prior history of e cessive bleeding following an e traction is important. In evaluating this history, one must consider the number of teeth e tracted, the location of teeth that were e tracted, the time of onset and duration of the hemorrhage, and the e tent of blood loss. Bleeding brought on by platelet abnormalities is li%ely to be immediate and to respond readily to direct pressure. While bleeding secondary to coagulation factor disorders may be delayed a few hours in onset and last for many days, often with recurrences. -o, thorough understanding and %nowledge about bleeding disorders is very much needed for dental professionals to minimi$e the complications of many treatment procedures.

52

References )C DavidsonRs Sprinciples and practice of medicine>)9 th editionK>3anslet, 1hilvers, Boon, 1olledge, 3unters. !C ;edical emergencies in the dental practice TmalammedK @th edition /C Bailey and :oveRs -hort practice of surgery>!/ rd editionK 'ussel, Williams, BulstrodeK ?C 1omplications in 2ral and ;a illofacial surgery>) st editionK Iaban, 0ogrel, 0errot. @C 1oncise ;edical 0hysiologyK>@th editionK 1haudhari <C -ystemic disease in dental treatment>)st editionK>;ichael.&.Tullman,

-pencer.W.'edding. 4C 1linical hematology>4th editionK>;a well.;.Wintrobe.

53

;# 666.he/o0hilia.org 0- 666.google.co/ 12Circu#!tin* f!ctor .III in i$itor: c!se re'ort !nd re"ie&.
M!+i##of!c Sur*. 4225 6e$789,4-:459:;. Re"ie& 3 Or!#

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Or!# Sur* Or!# Med Or!# P!t o# Or!# R!dio# Endod. 4224 M!r7 09,9-:4>;:52.

$#eedin*

1. 2. 3. ". %. (. *.

Human gene for factor VIII isolated. B-domain removed from factor VIII gene. B-domain-deleted (BDD) gene inserted into the production cells ( hinese hamster ovar! cells). BDD production cells gro#n in culture media that contain small amounts of human serum al$umin. BDD recom$inant factor VIII (BDDr&VIII) production cells are fro'en and stored. BDDr&VIII production cells are o$tained from the cell $an) and tha#ed. BDDr&VIII production cells gro# inside $ioreactors #ith human serum al$umin in the culture medium. +. ,e&acto is filtered a#a! from production cells and purified and concentrated $! a chromatograph! step. -. ,e&acto is processed through a viral solvent-detergent step. 1.. ,e&acto is processed through monoclonal anti$od! purification and three additional chromatograph! steps. 11. /o al$umin is added to the final formulation.

54