Hemophilia

Disroders of HemostasisDisroders of Hemostasis

•Vessel disorders• Henoch Schonlein Purpura

•Platelet disorders• Thrombocytopenia

•Factor disorders• Hemophilia

HemophiliaHemophilia

Congenital deficiency ofCongenital deficiency of

Factor VIII (Hemophilia A)Factor VIII (Hemophilia A)Or Or

Factor IX (Hemophilia B)Factor IX (Hemophilia B)

- CSN Vittal- CSN Vittal- CSN Vittal- CSN Vittal

Other Names & IncidencesOther Names & Incidences

• Hemophilia AHemophilia A 1 in 10,000 population1 in 10,000 population• Classic hemophilia Classic hemophilia

• Factor VIII deficiency Factor VIII deficiency

• Hemophilia B Hemophilia B 1 in 40,000 population 1 in 40,000 population• Christmas disease Christmas disease

• Factor IX deficiency Factor IX deficiency

• Hemophilia C Hemophilia C • Factor XI deficiency Factor XI deficiency

InheritanceInheritance

• X- Linked RecessiveX- Linked Recessive• Gene location Xq 28 – Hemophilia A Gene location Xq 28 – Hemophilia A • Gene location Xq 27.2 – Hemophilia B Gene location Xq 27.2 – Hemophilia B

• Sporadic mutation of gene 20-30%Sporadic mutation of gene 20-30%

. .

PhysiologyPhysiology

• F VIII is a glycoprotein procofactor synthesized and F VIII is a glycoprotein procofactor synthesized and released into the bloodstream by the vascular released into the bloodstream by the vascular endothelium. endothelium.

• In the circulating blood, it is mainly bound to von In the circulating blood, it is mainly bound to von Willebrand factor (vWF, also known as Factor VIII-Willebrand factor (vWF, also known as Factor VIII-related antigen) to form a stable complex. related antigen) to form a stable complex.

• Upon activation by thrombin or factor Xa, it dissociates Upon activation by thrombin or factor Xa, it dissociates from the complex to interact with Factor IXa the from the complex to interact with Factor IXa the coagulation cascade. coagulation cascade.

• It is a cofactor to Factor IXa in the activation of Factor X, It is a cofactor to Factor IXa in the activation of Factor X, which, in turn, with its cofactor Factor Va, activates more which, in turn, with its cofactor Factor Va, activates more thrombin. thrombin.

PhysiologyPhysiology

• No longer protected No longer protected by vWF, activated by vWF, activated Factor VIII is Factor VIII is proteolytically proteolytically inactivated inactivated (by activated (by activated Protein Protein CC and and Factor IXaFactor IXa) ) and quickly cleared and quickly cleared from the blood from the blood stream.stream.

• Factor VIII is Factor VIII is synthesized synthesized predominantly in the predominantly in the vascular vascular endothelium and is endothelium and is not affected by liver not affected by liver disease. disease.

PathophysiologyPathophysiology

• Factor VIIIFactor VIII has 2 components has 2 components• Factor VIII related antigen ( F VIII-Ag)Factor VIII related antigen ( F VIII-Ag)• Factor VIII coagulant activity ( F VIII-C)Factor VIII coagulant activity ( F VIII-C)

• Normally both these are in equal proportionNormally both these are in equal proportion

• In Carriers and hemophiliacs, Factor VIII C In Carriers and hemophiliacs, Factor VIII C is reduced while Factor VIII Ag is normalis reduced while Factor VIII Ag is normal



Degrees of Severity - Clinical Degrees of Severity - Clinical

DegreeDegree Factor VIII levelsFactor VIII levels SymptomsSymptomsMildMild 5 - 30%5 - 30%

> 0.05 to 0.25 IU / ml> 0.05 to 0.25 IU / ml

• AsymptomaticAsymptomatic

• Prolonged bleeding while tooth Prolonged bleeding while tooth extraction, extraction,

•severe trauma or following surgerysevere trauma or following surgery

ModerateModerate 1 - 4%1 - 4%> 0.01 to 0.05 IU / ml> 0.01 to 0.05 IU / ml

•Mild to moderate traumaMild to moderate trauma

SevereSevere < 1%< 1%< 0.01 IU / ml< 0.01 IU / ml

• Prolonged bleeding, Prolonged bleeding,

• Bleeding into joints and musclesBleeding into joints and muscles

• Severe mucosal bleedingSevere mucosal bleeding

• Excess bleeding from umbilical stumpExcess bleeding from umbilical stump

• Bleeding following circumcision Bleeding following circumcision

• Intra cranial bleedingIntra cranial bleeding

Symptoms of spontaneous bleeding Symptoms of spontaneous bleeding

• Many large or deep bruises Many large or deep bruises • Joint pain and swelling caused by internal bleeding Joint pain and swelling caused by internal bleeding • Unexplained bleeding or bruising Unexplained bleeding or bruising • Blood in your urine or stool Blood in your urine or stool • Prolonged bleeding from cuts or injuries, or after Prolonged bleeding from cuts or injuries, or after

surgery or tooth extraction surgery or tooth extraction • Nosebleeds with no obvious cause Nosebleeds with no obvious cause • Tightness in your joints Tightness in your joints

Emergency signs and symptoms of Emergency signs and symptoms of hemophiliahemophilia

• Sudden pain, swelling, and warmth of large joints, Sudden pain, swelling, and warmth of large joints, such as knees, elbows, hips and shoulders, and of the such as knees, elbows, hips and shoulders, and of the muscles of your arms and legs muscles of your arms and legs

• Bleeding from an injuryBleeding from an injury• Painful, lasting headache Painful, lasting headache • Repeated vomiting Repeated vomiting • Extreme fatigue Extreme fatigue • Neck pain Neck pain • Double vision Double vision

DiagnosisDiagnosis

• Platelet count normalPlatelet count normal

• Anemia – proportional to blood lossAnemia – proportional to blood loss

• CT, PTT – ProlongedCT, PTT – Prolonged

• Factor VIII or Factor IX decreasedFactor VIII or Factor IX decreased• By assay orBy assay or• By mixing study with normal plasma and By mixing study with normal plasma and

adsorbed plasmaadsorbed plasma

Mixing StudiesMixing Studies

• Normal serum contains : Factor IX, X, XI, XII

• Adsorbed plasma contains : Factor V, VIII, XI, XII

Correction of aPTT with Correction of aPTT with normal serumnormal serum but not with but not with adsorbed plasmaadsorbed plasma

Factor IXFactor IX deficiency deficiency

(Hemophelia B)(Hemophelia B)

Correction of aPTT with Correction of aPTT with adsorbed plasmaadsorbed plasma but not but not with with normal serumnormal serum

Factor VIIIFactor VIII deficiency deficiency

(Hemophelia A)(Hemophelia A)

ManagementManagement

• Principles of management: Principles of management: • Control or prevention of bleeding Control or prevention of bleeding

episodesepisodes

• Treatment of complicationsTreatment of complications

• RehabilitationRehabilitation

Prevention of BleedingPrevention of Bleeding

• Toys that do not have sharp edgesToys that do not have sharp edges• Using soft and stuffed toysUsing soft and stuffed toys• Padding the cribPadding the crib• Using upholsted furnitureUsing upholsted furniture• Using helmet, pads to protect elbows and kneesUsing helmet, pads to protect elbows and knees• Games like hockey, foot ball avoidedGames like hockey, foot ball avoided• Using soft or sponge tipped tooth brushes Using soft or sponge tipped tooth brushes • Proper advise on using sharp razorsProper advise on using sharp razors• Wear Medic Alert IDWear Medic Alert ID• Recognizing symptoms early Recognizing symptoms early

Therapeutic OptionsTherapeutic Options

• Fresh whole bloodFresh whole blood• Whole plasmaWhole plasma• Fresh Frozen PlasmaFresh Frozen Plasma• CryoprecipitateCryoprecipitate• Factor VIII ConcentrateFactor VIII Concentrate• Recombinant Factor VIII Recombinant Factor VIII

• From Hamster cultureFrom Hamster culture• Immuno affinity purifiedImmuno affinity purified

Replacement TherapyReplacement Therapy

• Replacing the clotting factor that’s too low or Replacing the clotting factor that’s too low or missing. missing.

• Concentrates of clotting factor VIII Concentrates of clotting factor VIII or or

• Clotting factor IX Clotting factor IX are slowly dripped in or injected into a vein. are slowly dripped in or injected into a vein.


• Complications of Replacement TherapyComplications of Replacement Therapy• Developing antibodiesDeveloping antibodies

• 20 percent of people with severe hemophilia A and 20 percent of people with severe hemophilia A and

• 1 percent of people with hemophilia B. 1 percent of people with hemophilia B.

• Viral infections from human clotting factors Viral infections from human clotting factors • Damage to joints, muscles etc. from delays in Damage to joints, muscles etc. from delays in

treatment treatment


• Fresh Frozen Plasma (FFP)Fresh Frozen Plasma (FFP)• Contains Factor VIII and / or Factor IX Contains Factor VIII and / or Factor IX • 1 Unit of FFP = 200 units of F-VIII or F - IX1 Unit of FFP = 200 units of F-VIII or F - IX

• CryoprecipitateCryoprecipitate from single donor contains from single donor contains F- VIII, vonWillibrand Factor and fibrinogen F- VIII, vonWillibrand Factor and fibrinogen• 1 Unit of Cryoprecipitate = 100 units of F-VIII or 1 Unit of Cryoprecipitate = 100 units of F-VIII or

F – IX F – IX

Each Unit of Factor VIII or IX = activity of 1 ml of normal plasma

Prophylactic TherapyProphylactic Therapy

• During surgeryDuring surgery

• After traumaAfter trauma

Dose CalculationDose Calculation

• 20 U / kg of factors - increase the 20 U / kg of factors - increase the level by ~ 0.5 ml or 50%level by ~ 0.5 ml or 50%

Clinical Situation Factor VIII level should be raised to

Minor bleedsMinor bleeds

(knee & elbow bleeds)(knee & elbow bleeds)

20 – 40 %20 – 40 %

In major & life threatening conditions In major & life threatening conditions

(hip bleeds, intracranial hemorrhages, (hip bleeds, intracranial hemorrhages, bleeding around airways)bleeding around airways)

to be raised to 100% to be raised to 100% (100 U/ml)(100 U/ml)

Treatment of HemophiliaTreatment of Hemophilia

• Half life of Factors:Half life of Factors:

Factor VIII Factor IX

1st Dose 6-8 hrs 4-6 hrs

Subsequent Dose

8-12 hrs 18-24 hrs

Drug Therapy in HemophiliaDrug Therapy in Hemophilia

• EACAEACA ( ( –amino caproic acid): –amino caproic acid): • Inhibitor of fibrinolytic enzyme, inhibits clot Inhibitor of fibrinolytic enzyme, inhibits clot

lysis and promotes hemostasis in oral bleeds lysis and promotes hemostasis in oral bleeds and other sites.and other sites.

• Contraindication : Renal bleedsContraindication : Renal bleeds

Drug TherapyDrug Therapy

• DesmopressinDesmopressin : : • DDAVP stimulates the release of stored DDAVP stimulates the release of stored factor VIII factor VIII and and von von

Willebrand factorWillebrand factor • Increases the level of these proteins in your blood. Increases the level of these proteins in your blood.

Von Willebrand factor carries and binds factor VIII, which then can Von Willebrand factor carries and binds factor VIII, which then can stay in the bloodstream longer. stay in the bloodstream longer.

• Administration : Injection or Nasal spray. Administration : Injection or Nasal spray. • Use:Use:

• Before dental work Before dental work • For treating bleeding from the mouth or nose For treating bleeding from the mouth or nose • For mild intestinal bleeding For mild intestinal bleeding

Drug Therapy – Other DrugsDrug Therapy – Other Drugs

• Danazol :Danazol :

• Fibrin glue :Fibrin glue : Useful for controlling bleeding Useful for controlling bleeding at surgical and orthopedic surgical sites. at surgical and orthopedic surgical sites. • It consists of a mixture of fibrinogen, thrombin, It consists of a mixture of fibrinogen, thrombin,

and FXIII to cross-link freshly formed fibrin. and FXIII to cross-link freshly formed fibrin. • Useful in patients with an inhibitor to FVIII. Useful in patients with an inhibitor to FVIII.

ComplicationsComplications

• Due to diseaseDue to disease• ArthropathyArthropathy• Destruction of jointsDestruction of joints

• Due to treatmentDue to treatment• Hepatitis CHepatitis C• Allergic reactionsAllergic reactions• HemolysisHemolysis• HIV transmissionHIV transmission• ThrombosisThrombosis

Long Term ManagementLong Term Management

Interdisciplinary CareInterdisciplinary Care• Families need psychological supportFamilies need psychological support

• Genetic counselingGenetic counseling

• Antenatal diagnosisAntenatal diagnosis

• Multispecialistic approachMultispecialistic approach

• Genetic CounselingGenetic Counseling

• Hemophilic associationsHemophilic associations

• VittalVittal

Thank YouThank You

Health & Medicine

Hemophilia