Bleeding DisordersBleeding Disorders

JANUARY 19, 2012JANUARY 19, 2012Erin M. KwolekErin M. Kwolek

3 important questions…3 important questions…

Is the bleeding significant?Is the bleeding significant?

Is the bleeding likely related to an Is the bleeding likely related to an underlying health problem or to underlying health problem or to medication/chemical ingestion?medication/chemical ingestion?

Is there a family history of a Is there a family history of a bleeding disorder?bleeding disorder?

Important historical Important historical informationinformation

The nature of bruisingThe nature of bruising

Site of bleedingSite of bleeding

Bleeding with traumaBleeding with trauma

Duration of bleeding tendencyDuration of bleeding tendency

General healthGeneral health

Drug and chemical ingestionDrug and chemical ingestion

Family history of bleedingFamily history of bleeding

hemophiliahemophilia

1.1. HemophiliaHemophilia

2.2. PorphyriaPorphyria

3.3. HIV/AIDSHIV/AIDS

4.4. SmallpoxSmallpox

5.5. PlaguePlague

6.6. CholeraCholera

7.7. TuberculosisTuberculosis

8.8. SyphillisSyphillis

9.9. InfluenzaInfluenza

10.10. MalariaMalaria

11.11. Yellow FeverYellow Fever

12.12. Irish Potato BlightIrish Potato Blight

Hemophilia AHemophilia Ahistoryhistory

Talmud – babies did not have to be Talmud – babies did not have to be circumcised if two brothers had circumcised if two brothers had died from the proceduredied from the procedure

1803 – “hemorrhagic disposition 1803 – “hemorrhagic disposition existing in certain families”existing in certain families”

1828 - hemophilia1828 - hemophilia

HemophiliaHemophiliaseverityseverity

Factor VII or IX level

Severity Type of bleeding

<0.01 IU/mL Severe Spontaneous, minimal trauma, young age

0.01 – 0.05 IU/mL(1-5%)

Moderate With trauma or surgery, can be spontaneous

0.06 – 0.40 IU/mL(6-40%)

Mild Only with trauma or surgery, can present in adulthood

Hemophilia AHemophilia AFactor VIIIFactor VIII

1:10,0001:10,000

Classic hemophilia, Royal diseaseClassic hemophilia, Royal disease

Hemophilia BHemophilia BFactor iXFactor iX

1:60,0001:60,000

Christmas diseaseChristmas disease

Hemophilia Hemophilia treatmenttreatment

Replace missing clotting factorsReplace missing clotting factors

Education and lifestyleEducation and lifestyle

On demand vs. ProphylacticOn demand vs. Prophylactic

Clotting factors in Clotting factors in canadacanada

Product Introduction in Canada

Fresh whole blood 1947

Cryoprecipitate (Factor VIII) 1965

Factor VIII (lyophilized, unheated) 1968

Factor VIII (lyophilized, dry heat-treated)Factor IX (lyophilized, dry heat-treated)

19851985

Factor VIII (viral inactivation: vapour heat, solvent detergent)

1987

High purity factor VIII (monoclonal antibody purified)Purity factor IX

19871991

GE recombinant factor VIII concentrateGE recombinant factor IX concentrate

19931998

Von willebrandVon willebrand

Von Willebrand factor is made and Von Willebrand factor is made and stored in endothelial cellsstored in endothelial cells

Anchors platelets to subendotheliumAnchors platelets to subendothelium

Factor is made up of protein multimers Factor is made up of protein multimers – the more repeating units the – the more repeating units the “stickier” (more effective) the factor “stickier” (more effective) the factor is is

Stabilizes factor VIII in plasmaStabilizes factor VIII in plasma

VW Dx severityVW Dx severity

TYPE 1 – partial quantitative TYPE 1 – partial quantitative deficiencydeficiency• 80% of people with VW Dx have type 180% of people with VW Dx have type 1

TYPE 2 – qualitative defectTYPE 2 – qualitative defect

TYPE 3 – virtually complete TYPE 3 – virtually complete quantitative deficiencyquantitative deficiency• Very rareVery rare• First type describedFirst type described

Variable expressivity and incomplete penetranceVariable expressivity and incomplete penetrance

Von willebrandVon willebrandtreatmenttreatment

Exogenous - DesmopressinExogenous - Desmopressin• ~3x increase in plasma VWF and factor ~3x increase in plasma VWF and factor

VIIIVIII• Not useful if qualitative abnormality (type Not useful if qualitative abnormality (type

2)2)• Not useful if complete deficiency (type 3)Not useful if complete deficiency (type 3)

Endogenous – factorsEndogenous – factors• Plasma derived VWF concentrate – Plasma derived VWF concentrate –

contains VWF and factor VIIIcontains VWF and factor VIII

Hemophilia A Hemophilia B Von Willebrand

Inheritance X-linked X-linked autosomal dominant

Deficiency Factor VIII Factor IV VW factor, VIIIC

Bleeding sites muscle, joint muscle, joint mucous membranes, skin, menstrual

PT normal normal normal

PTT prolonged prolonged prolonged or normal

Bleeding time normal normal prolonged or normal

Factor VIII activity

low normal low or normal

VW factor antigen

normal normal low

VW factor activity

normal normal low

Factor IX normal low normal

Platelet aggregation

normal normal normal

Hemophilia A Hemophilia B Von Willebrand

Inheritance X-linked X-linked autosomal dominant

Deficiency Factor VIII Factor IV VW factor, VIIIC

Bleeding sites muscle, joint muscle, joint mucous membranes, skin, menstrual

PT normal normal normal

PTT prolonged prolonged prolonged or normal

Bleeding time normal normal prolonged or normal

Factor VIII activity

low normal low or normal

VW factor antigen

normal normal low

VW factor activity

normal normal low

Factor IX normal low normal

Platelet aggregation

normal normal normal

Hemorrhagic disease of Hemorrhagic disease of the newbornthe newborn

Normal PTT, prolonged PTNormal PTT, prolonged PT

VKDB – early, classic, lateVKDB – early, classic, late

Prophylactic Vitamin KProphylactic Vitamin K

Intracranial VKDBIntracranial VKDB

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ThrombocytopeniaThrombocytopenia

Decreased productionDecreased production

Increased destructionIncreased destruction

Abnormal sequestrationAbnormal sequestration

Normal value – 150-400 x 10Normal value – 150-400 x 1099/L/L

Lifespan 7-10dLifespan 7-10d

ThrombocytopeniaThrombocytopeniadecreased productiondecreased production

Toxins/drugs/alcoholToxins/drugs/alcohol

Aplastic anemiaAplastic anemia

Intrinsic bone marrowIntrinsic bone marrow

DisplacementDisplacement

Nutritional deficiencyNutritional deficiency

Hereditary thrombocytopeniasHereditary thrombocytopenias

ThrombocytopeniaThrombocytopeniaIncreased destructionIncreased destruction

Auto Immune - ITPAuto Immune - ITP

ThrombocytopeniaThrombocytopenianon-immunenon-immune

DICDIC

TTPTTP

VasculitisVasculitis

HELLPHELLP

DICDIC

Activation of coagulation – failure of Activation of coagulation – failure of homeostasis with bleeding and/or homeostasis with bleeding and/or thrombosis; consumption of clotting thrombosis; consumption of clotting factors and plateletsfactors and platelets

InfectionInfection

TraumaTrauma

Abnormal endothelial surfaceAbnormal endothelial surface

CancerCancer

Obstetrical complicationsObstetrical complications

ThrombocytopeniaThrombocytopeniaIncreased sequestrationIncreased sequestration

SplenomegalySplenomegaly

Platelet dysfunctionPlatelet dysfunction

Congenital causes are rare!Congenital causes are rare!• Glanzmann thrombastheniaGlanzmann thrombasthenia

• Glycoprotein IIb/IIIaGlycoprotein IIb/IIIa• Bernard-Soulier syndromeBernard-Soulier syndrome

• Glycoprotein Ib/IX/VGlycoprotein Ib/IX/V

AcquiredAcquired• DrugsDrugs• Renal diseaseRenal disease• Bone marrow disordersBone marrow disorders

3 important questions…3 important questions…

Is the bleeding significant?Is the bleeding significant?

Is the bleeding likely related to an Is the bleeding likely related to an underlying health problem or to underlying health problem or to medication/chemical ingestion?medication/chemical ingestion?

Is there a family history of a Is there a family history of a bleeding disorder?bleeding disorder?