Hemophilia & von willibrand Hemophilia & von willibrand diseasedisease

Dr.PadmashiniDr.Padmashini

objectivesobjectives

History History IntroductionIntroduction Definition Definition Clinical Features Clinical Features Diagnosis Diagnosis Available treatment modalitiesAvailable treatment modalities

History History

Best known of the Best known of the hereditary bleeding hereditary bleeding disorders.disorders.

First coined by First coined by Schonlein Schonlein in in 1820s. 1820s.

Originally termed Originally termed ““Haemorraphilia”Haemorraphilia” i.e. love i.e. love for haemorrhages but over for haemorrhages but over time contracted to time contracted to Hemophilia.Hemophilia.

Hemophilia is often called the disease of kings because it was Hemophilia is often called the disease of kings because it was carried by many members of Europe’s royal family. carried by many members of Europe’s royal family.

Queen VictoriaQueen Victoria of England was a carrier of hemophilia of England was a carrier of hemophilia

Introduction Introduction

Hemophilia are bleeding disorders due to deficiency or defect Hemophilia are bleeding disorders due to deficiency or defect in one of the factor present in clotting cascade,in one of the factor present in clotting cascade,

X – linked recessive disorder,X – linked recessive disorder,

Disease of men with women being asymtomatic carrierDisease of men with women being asymtomatic carrier

Definition Definition

Hemophilia A (classic) :Hemophilia A (classic) : deficiency or dysfunction of factor deficiency or dysfunction of factor VIII VIII

It is a large single chain protein that regulates the activation of It is a large single chain protein that regulates the activation of factor X by proteases generated in intrinsic coagulation factor X by proteases generated in intrinsic coagulation pathwaypathway

Incidence : 1 in 10,000malesIncidence : 1 in 10,000males

Hemophilia B (Christmas)Hemophilia B (Christmas) : : deficiency or dysfunction of deficiency or dysfunction of factor IXfactor IX

Incidence : 1 in 25,000-35,000 malesIncidence : 1 in 25,000-35,000 males

Von willibrand diseaseVon willibrand disease : : It is a hereditary deficiency a defect It is a hereditary deficiency a defect in portion of factor VIII complexin portion of factor VIII complex

TypesTypes

Factor level Factor level < 1%< 1% - severe disease - severe disease

Factor level Factor level 1-5%1-5% - moderate disease - moderate disease

Factor level Factor level 5-20 %5-20 % - mild disease - mild disease

Factor level Factor level 20-50%20-50% - unaware that they have hemophilia - unaware that they have hemophilia

Easy bruising & recurrent Easy bruising & recurrent bleeding in to joints & bleeding in to joints & musclesmuscles

Bleeding occurs hrs or days Bleeding occurs hrs or days after injury if untreated after injury if untreated continue for days or weekscontinue for days or weeks

Clinical featuresClinical features

Large collection of clotted Large collection of clotted blood putting pressure on blood putting pressure on adjacent normal tissue-adjacent normal tissue-necrosis of muscle – necrosis of muscle – compartment syndromecompartment syndrome

Pseudophlebitis :Pseudophlebitis : venous venous congestioncongestion

Pseudotumour :Pseudotumour : bone cysts bone cysts result from unresolved result from unresolved hematomahematoma

CNSCNS : SDH occur : SDH occur spontaneously or with spontaneously or with minimal traumaminimal trauma

HematuriaHematuria : common : common usually not serioususually not serious

Femoral neuropathyFemoral neuropathy due to due to pressure from unsuspected pressure from unsuspected retroperitoneal hematomaretroperitoneal hematoma

Mucocutaneous bleedingMucocutaneous bleeding: : spontaneous bleeding in to spontaneous bleeding in to orophraynx , GI tract, orophraynx , GI tract, epistaxsis ,hemoptysis, epistaxsis ,hemoptysis, delayed bleeding after dental delayed bleeding after dental extractionextraction

Hemophilic Arthropathy:Hemophilic Arthropathy: chronic inflammation. chronic inflammation. Chronic proliferative synovitisChronic proliferative synovitis characterised by progressive and erosive destruction of joint characterised by progressive and erosive destruction of joint

cartilage, narrowing of joint spacecartilage, narrowing of joint space

scenarioscenario

A one yr old male baby brought to ER at around 4 pm with A one yr old male baby brought to ER at around 4 pm with bleeding continously after a small cut in the knee joint while bleeding continously after a small cut in the knee joint while playing at around 11am on the same day playing at around 11am on the same day

Lab InvestigationLab Investigation

COAGULATION PROFILECOAGULATION PROFILE PT – normalPT – normal

aPTT – prolongedaPTT – prolonged

Factor assayFactor assay

factor VIII deficiency – hemophilia Afactor VIII deficiency – hemophilia A

factor IX deficiency – hemophilia B factor IX deficiency – hemophilia B

Bleeding time - normalBleeding time - normal

Prenatal diagnosisPrenatal diagnosis

Obtain chorionic villi samples in 10th-11th gestational week and perform direct genotype testing.

Initial assesmentInitial assesment

Early & complete factor replacement before or at the same time as other resuscitative & diagnostic maneuvers

Bleeding in to neck,tongue,retropharynx – airway compromise – intubation

Bleeding in to CNS – immediate factor replacement fallowed by CT scan

Cont..Cont..

Neurologic defecitNeurologic defecit localize to region with in localize to region with in spinal cord – spinal cord – MRIMRI

Hemophilic pt with back, thigh, groin, abdominal pain-factor Hemophilic pt with back, thigh, groin, abdominal pain-factor replacement with imagingreplacement with imaging

Hemarthrosis Hemarthrosis – consult orthopedist for splinting & – consult orthopedist for splinting & rehabilitationrehabilitation

Special attentionSpecial attention

Adequate pain relief with opiods

Avoid aspirin & NSAID

DONTS

Central lines should not be placed with out factor replacement

ABG/ arterial line

IM injections

TreatmentTreatment

Factor replacement therapyFactor replacement therapy

Two different optionsTwo different options : :

Plasma derived & purified factorPlasma derived & purified factor

Recombinant factor replacementRecombinant factor replacement

Hemophilia AHemophilia A Human plasma derived factor VIII productsHuman plasma derived factor VIII products Human plasma derived factor VIIHuman plasma derived factor VII Recombinant factor VIII productsRecombinant factor VIII products Porcine factor VIII productsPorcine factor VIII products

Hemophilia BHemophilia B

Factor IX complex productFactor IX complex product Activated factor IX complex productActivated factor IX complex product Purified factor IX productPurified factor IX product Recombinant factor IX productRecombinant factor IX product

DOSAGEDOSAGE

Dosing regimen based on Dosing regimen based on clotting factor volumeclotting factor volume of distribution, of distribution,

half life of factor & hemostatic level of factorhalf life of factor & hemostatic level of factor required to control required to control

the bleedingthe bleeding

Hemophilia AHemophilia A

One unit of factor VIII per Kg of body weight raises plasma level by approximately0.02U/ml

Half life – 8-12 hrs

Dose of FVIII (units) = (percent desired rise in plasma FVIII) x (body wt) x 0.5

Hemophilia BHemophilia B

One unit of factor IX per Kg of body weight raise the plasma One unit of factor IX per Kg of body weight raise the plasma level by0.01u/mllevel by0.01u/ml

Half life – 16 hrsHalf life – 16 hrs

Dose of factor IX(units)=(percent desired rise in factor IX) X Dose of factor IX(units)=(percent desired rise in factor IX) X body weightbody weight

FACTOR REPLACEMENT GUIDELINESFACTOR REPLACEMENT GUIDELINES

40-50% 80-40-50% 80-100%100%

50% 100%50% 100%

30-50% 100%30-50% 100%

Minimum initial factor levelsMinimum initial factor levels

Undiagnosed bleeding disorderUndiagnosed bleeding disorder

FFP or cryoprecipitateFFP or cryoprecipitate

Each bag cryoprecipitate:Each bag cryoprecipitate: 100 units of factor VIII100 units of factor VIII

FFP – all plasma clotting FFP – all plasma clotting factor ,concentration of factor ,concentration of 1u/ml1u/ml

One unit FFP – raise factor One unit FFP – raise factor level 3-5 %level 3-5 %

CryoprecipitateCryoprecipitate

Prepared by slowly thawing fresh frozen plasma at 2-4Prepared by slowly thawing fresh frozen plasma at 2-4 `̀C, then C, then harvesting the precipitate by centrifugation.harvesting the precipitate by centrifugation.

Cryo prepared from 200ml of FFP contains 80-100 U of Cryo prepared from 200ml of FFP contains 80-100 U of FVIII, ~250mg fibrinogen and useful amounts of FXIII and FVIII, ~250mg fibrinogen and useful amounts of FXIII and vWF per 10-15ml of precipitate.vWF per 10-15ml of precipitate.

Use thawed cryo within 4hr.Use thawed cryo within 4hr.

Can be stored at -18`C for 1yr.Can be stored at -18`C for 1yr.

scenarioscenario

A 10 yr old girl weighing 20kg a known case of haemophilia A 10 yr old girl weighing 20kg a known case of haemophilia B came to ER with complaints of profuse gum bleeding after B came to ER with complaints of profuse gum bleeding after brushing her teethbrushing her teeth

Specific problemsSpecific problems

Oral & mucosal bleeding :Oral & mucosal bleeding :

Area identified, cleaned of Area identified, cleaned of inadequate clot & dry inadequate clot & dry topical thrombin placed at topical thrombin placed at bleeding sitebleeding site

Factor replacement should Factor replacement should be 80-100 %be 80-100 %

Antifibrinolytic agent( Antifibrinolytic agent( epsolin aminocarporic acid & epsolin aminocarporic acid & tranexamic acid)tranexamic acid)

Dose of EACA – 75-100 mg/kg q 6 h (children)Dose of EACA – 75-100 mg/kg q 6 h (children)

1-6 g q 6 h for adults1-6 g q 6 h for adults

Given PO /IVGiven PO /IV

Tranexamic acidTranexamic acid oral- 25 mg/kg/dose oral- 25 mg/kg/dose

every 6-8hr.every 6-8hr. iv - 10 mg/kg/dose iv - 10 mg/kg/dose

every 6-8hrevery 6-8hr

Topical hemostatic agentTopical hemostatic agent – – microfibrillar collagen microfibrillar collagen hemostat,thrombin & hemostat,thrombin & absorbable gelatin spongesabsorbable gelatin sponges

scenarioscenario

A 25 yr old gentleman who is diagnosed as having A 25 yr old gentleman who is diagnosed as having haemophilic A 10 yrs ago, with factor level of 25% admited in haemophilic A 10 yrs ago, with factor level of 25% admited in the hospital for severe AGE,while securing I.V cannula pt had the hospital for severe AGE,while securing I.V cannula pt had continous bleeding from the vene puncture site continous bleeding from the vene puncture site

Mild hemophilia AMild hemophilia A

Treated with desmopressinTreated with desmopressin

DesmopressinDesmopressin cause release cause release of Vwf from endothelial siteof Vwf from endothelial site

Inc amount of Vwf capable Inc amount of Vwf capable of carrying additional of carrying additional amount of factor VIII in amount of factor VIII in plasmaplasma

DoseDose

Intravenous:Intravenous: 0.3 ug/kg ( max 20 ug) over 30 min 0.3 ug/kg ( max 20 ug) over 30 min

Intra nasal :Intra nasal : children > 5 yrs single spray in single nostril (150 children > 5 yrs single spray in single nostril (150 ug total dose)ug total dose)

Adults & adolescent 300 ug total doseAdults & adolescent 300 ug total dose

Third dose – inc factor by 2-3 timesThird dose – inc factor by 2-3 times

Repeated 8-12 hrsRepeated 8-12 hrs

Pts stores of factor VIII will be depleted & subsequently effect Pts stores of factor VIII will be depleted & subsequently effect will be lesswill be less

ScenarioScenario

A 7yr old boy who is an haemophilic came to ER with A 7yr old boy who is an haemophilic came to ER with complains of tooth ache O/E pt was having caries tooth,for complains of tooth ache O/E pt was having caries tooth,for which dentist has adviced tooth extractionwhich dentist has adviced tooth extraction

Dental procedureDental procedure

Filling carries toothFilling carries tooth : single : single infusion of factor VIII with infusion of factor VIII with administration of 4-6 g of administration of 4-6 g of EACA q6h for 3-4 daysEACA q6h for 3-4 days

Major oral & periodontalMajor oral & periodontal surgery , extraction of surgery , extraction of permanent teeth – factor permanent teeth – factor replacement replacement begin before begin before surgery & continue for 2-3 surgery & continue for 2-3 daysdays

InhibitorsInhibitors

Usually IgG antibodies that rapidly neutralize factor VIII Usually IgG antibodies that rapidly neutralize factor VIII activityactivity

Two typesTwo types : :

Type 1Type 1 – raise their antibody fallowing exposure to factor VIII – raise their antibody fallowing exposure to factor VIII

Type 2Type 2 – low antibody titre not stimulated by factor VIII – low antibody titre not stimulated by factor VIII infusioninfusion

Type 1Type 1 – should not receive factor VIII – should not receive factor VIII

Control of bleedingControl of bleeding – porcine factor VIII – porcine factor VIII

-prothrombin complex concentrate-prothrombin complex concentrate

Type 2Type 2 – respond to higher doses of factor VIII – respond to higher doses of factor VIII

Gene therapyGene therapy – –Involves transfer of genes that express a Involves transfer of genes that express a particular gene product into human cells particular gene product into human cells

studies in human under trial studies in human under trial

ComplicationComplication

Multiple episodes of hepatitisMultiple episodes of hepatitis

Elevated hepatocellular enzyme levelElevated hepatocellular enzyme level

HepatospleenomegalyHepatospleenomegaly

End stage liver diseaseEnd stage liver disease

Iv drug abusers & long term hemophilia – high risk for AIDSIv drug abusers & long term hemophilia – high risk for AIDS

Von willibrand diseaseVon willibrand disease

It is a hereditary deficiency a defect in portion of factor VIII It is a hereditary deficiency a defect in portion of factor VIII complexcomplex

vWF is a glycoprotien ,synthesized, stored & then secreted by vWF is a glycoprotien ,synthesized, stored & then secreted by vascular endothelial cellsvascular endothelial cells

Co factor for platelet adhesion & carrier protien for factor VIIICo factor for platelet adhesion & carrier protien for factor VIII

Major three groupsMajor three groups

Type 1 :Type 1 : common & partial quantitiative disease common & partial quantitiative disease

Type 2Type 2 : qualitative ( abnormal function) : qualitative ( abnormal function)

Type 3Type 3 : severe & almost compelete defeciency of vWF : severe & almost compelete defeciency of vWF

Clinical featuresClinical features

Skin & mucosal bleedingSkin & mucosal bleeding Recurrent epistaxsis,gingival bleedingRecurrent epistaxsis,gingival bleeding Unusual bruisingUnusual bruising GI bleedingGI bleeding Menorrhagia in young womenMenorrhagia in young women

Laboratory testLaboratory test

Prolonged bleeding timeProlonged bleeding time Low or normal vWF antigenLow or normal vWF antigen Low vWF activityLow vWF activity Mildly prolonged aPTTMildly prolonged aPTT Pt with O bld group – 30 % reduction in vWF level compared Pt with O bld group – 30 % reduction in vWF level compared

to other bld groupsto other bld groups

TreatmentTreatment

Non transfusional therapyNon transfusional therapy : : DesmopressinDesmopressin – mainstay of treatment with type 1 vWF – mainstay of treatment with type 1 vWF It induces release of vWF from storage site with in the It induces release of vWF from storage site with in the

endotheliumendothelium Dose Dose

Transfusional therapiesTransfusional therapies

Plasma derivativesPlasma derivatives CryoprecipitateCryoprecipitate Humate pHumate p Platlelet transfusionPlatlelet transfusion

Prevention of bleedingPrevention of bleeding Avoid traumaAvoid trauma by adjusting by adjusting

their lifestyletheir lifestyle..

Contact sports should be Contact sports should be avoided, but avoided, but swimming and swimming and cyclingcycling with appropriate with appropriate gear should be encouragedgear should be encouraged..

AvoidAvoid use of drugs that use of drugs that affect platelet functionaffect platelet function viz. viz. NSAIDsNSAIDs..

What medical information should be carried by a What medical information should be carried by a hemophiliachemophiliac ? ?

A person with hemophilia should A person with hemophilia should carrycarryinformation about his health, includinginformation about his health, includingthe type of hemophilia, treatmentthe type of hemophilia, treatmentneeded, and allergies.needed, and allergies.

An international medical card isAn international medical card isavailable free through the Worldavailable free through the WorldFederation of Hemophilia. Tags calledFederation of Hemophilia. Tags calledMedic-Alert and Talisman are sold inMedic-Alert and Talisman are sold insome countriessome countries

World Hemophilia Day 2009World Hemophilia Day 2009  

Since 1989, patient groups and treatment centres have been Since 1989, patient groups and treatment centres have been coming together on coming together on April 17 to celebrate World Hemophilia April 17 to celebrate World Hemophilia Day.Day.

The theme for World Hemophilia Day 2009 is The theme for World Hemophilia Day 2009 is “Together, we “Together, we carecare,” which emphasizes the importance of comprehensive ,” which emphasizes the importance of comprehensive care in hemophilia healthcare delivery. care in hemophilia healthcare delivery.

Take home messageTake home message

Early & complete factor replacement

Do not waste time in imaging studies

Prevention of bleeding

The Sun is Rising for Patients with Hemophilia

The Future is Bright

Thank

you