case 01 plate let disorders

7/28/2019 Case 01 Plate Let Disorders

1/41

Case Studies

inClinical

Hemostasis

Case StudiesCase Studies

ininClinicalClinical

HemostasisHemostasis


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Case Studiesin

ClinicalHemostasis

Case StudiesCase Studiesinin

ClinicalClinicalHemostasisHemostasis

Case #1Patient J.M.

Case #1Case #1Patient J.M.Patient J.M.


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Patient J.M.Patient J.M.Patient J.M.

! Middle-aged man admitted for elective

cholecystomy! Two previous dental extractions associated

with rebleeding requiring repacking

! History of easy bruising and occasional

nosebleeds! No other operative procedures

! No history of trauma

! Family history negative for bleeding andthrombosis

! Physical examination unremarkable except forabdominal tenderness







! Family history negative for bleeding andthrombosis

! Physical examination unremarkable except forabdominal tenderness


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q

PLTS0

100

200

300

400

500

600

THOU

/uL q

PT0

5

10

15

20

Seco

nds

q

APTT

20

25

30

35

40

45

50

Seconds

q

Bleeding Time0

5

10

15

20

Minu

tes


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Primary & Secondary HemostasisPrimary & Secondary Hemostasis

Primary HemostasisPlatelet Adhesion & Aggregation

Platelet Plug Formation

Primary HemostasisPlatelet Adhesion & Aggregation

Platelet Plug Formation

Secondary HemostasisCoagulation

Platelet Plug Stabilization

Secondary HemostasisCoagulation

Platelet Plug Stabilization


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Platelet StructurePlatelet StructurePlatelet Structure

Surface receptorsSurface receptors

Glycogen granulesGlycogen granulesCell membraneCell membrane

Surface canalicular systemSurface canalicular system

-granules-granulesMicrotubulesMicrotubules

MitochondriaMitochondria LysozymesLysozymes

Dense bodiesDense bodies


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PlateletFunction

PlateletPlatelet

FunctionFunction

Secondary AggregationSecondary Aggregation

Damaged Vessel WallDamaged Vessel Wall

Platelet AdhesionPlatelet Adhesion

Platelet Shape Change

Primary Aggregation

Platelet Shape Change

Primary Aggregation

Metabolic Events

Degranulation

Metabolic Events

Degranulation


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Restingplatelet Activated platelet

with FbR

Doublet andmultiplet formation

Platelet ActivationPlatelet ActivationPlatelet Activation

ADP


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Platelet membranePlatelet membrane

GPIIbIIIaGPIIbIIIaGPIbGPIb

Adhesion siteAdhesion siteAggregation, vWF, andfibrinogen binding site

Aggregation, vWF, andfibrinogen binding site

vWFvWF VIII:CVIII:C

Subendothelialcollagen

Subendothelialcollagen

PLTFunction

PLT

Function


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Sources of vWFSources of vWFSources of vWF

PlateletsPlatelets

-Granule (LMW)-Granule (LMW)

Endothelial CellEndothelial Cell

Weibel-Palade

Body (HMW)

Weibel-Palade

Body (HMW)


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Membrane

Phospholipids

Membrane

Phospholipids

PlateletAggregation

TxA2

ThromboxaneSynthetase

Arachidonic Acid

Cyclo-oxygenase

Phospholipase

CyclicEndoperoxidases

Dense

Granules

ADP

Membrane

Glycoprotein

Platelet

Metabolism

Platelet

Metabolism

TxA2

PlateletAgonistsPlatelet

Agonists


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Platelet Aggregation StudiesPlatelet Aggregation StudiesPlatelet Aggregation Studies

Incubate 10 minutesMeasure light transmission

Incubate 10 minutesMeasure light transmission

Aggregated plateletsAggregated plateletsPlatelet rich plasmaPlatelet rich plasma

Platelet agonist*

* Platelet agonists - ADP, epinephrine, collagen

ristocetin, arachidonic acid, thrombin

* Platelet agonists - ADP, epinephrine, collagen

ristocetin, arachidonic acid, thrombin


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Platelet AggregationPlatelet AggregationPlatelet Aggregation

Light

Primary

Aggregation

Time

ShapeChange

SecondaryAggregation


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Normal AggregationNormal AggregationNormal Aggregation

0

20

40

60

80

100

0 2 4 6 8 10

Time (Minutes)

0

20

40

60

80

100

0 2 4 6 8 10

Time (Minutes)

0

20

40

60

80

100

0 2 4 6 8 10

Time (Minutes)

0

20

40

60

80

100

0 2 4 6 8 10

Time (Minutes)

ADP - 1M

ADP - 1M

ADP - 1M

COLL RIST

EPI 5M

ADP EPI

Ristocetin 1.2 mg/mLCollagen 2 g/mL


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CoagulationCoagulationCoagulationProthrombinProthrombin

FibrinFibrinFibrinogenFibrinogen

ThrombinThrombin


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CoagulationCoagulationCoagulation

TissueFactor

TissueFactor

ProthrombinProthrombin


ThrombinThrombin

FactorXII

FactorXII

Extrinsic

Pathway

Extrinsic

Pathway

Intrinsic

Pathway

Intrinsic

Pathway

VaVIIIaXa

VaVIIIaXa

VaVIIIaXa

VaVIIIaXa


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XX XaXa

ProthrombinProthrombin ThrombinThrombin

XIaXIa

IXIX

XIXI

Contact

Factors

Contact

Factors

VV

VIIVII

Modern Concept

of Coagulation

Modern Conceptof Coagulation

IXaIXa

VIIIVIII

TissueFactor

TissueFactor

InjuredTissue

VIIVII

- Charged

Surface


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TissueFactor

TissueFactor



ThrombinThrombin

FactorXII

FactorXII

Extrinsic

Pathway

Extrinsic

Pathway

Intrinsic

Pathway

Intrinsic

Pathway

ProthrombinTime

VaVIIIaXa

VaVIIIaXa

VaVIIIaXa

VaVIIIaXa


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Prothrombin

Time (PT)


Time (PT)Time (PT)

ThromboplastinCa++

ThromboplastinCa++

Fibrinclot

FibrinclotIncubateIncubate

Platelet-

richplasma

Platelet-

richplasma


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TissueFactor

TissueFactor



ThrombinThrombin

FactorXII

FactorXII

Extrinsic

Pathway

Extrinsic

Pathway

Intrinsic

Pathway

Intrinsic

Pathway

VaVIIIaXa

VaVIIIaXa

VaVIIIaXa

VaVIIIaXa

Activated PartialThromboplastic

Time (aPTT)


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Activated Partial

ThromboplastinTime (aPTT)

Activated PartialActivated Partial

ThromboplastinThromboplastinTime (aPTT)Time (aPTT)

Partial

ThromboplastinPlatelet ActivatorCa++

PartialThromboplastin

Platelet ActivatorCa++

Fibrinclot

Fibrinclot

IncubateIncubate

Platelet-

richplasma

Platelet-

richplasma


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! Family history negative for bleeding and

thrombosis! Physical examination unremarkable except for

abdominal tenderness

! Middle-aged man admitted for electivecholecystomy

! Two previous dental extractions associatedwith rebleeding requiring repacking




! Family history negative for bleeding and

thrombosis! Physical examination unremarkable except for

abdominal tenderness


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Defects of HemostasisDefects of HemostasisDefects of Hemostasis

BleedingBleeding ThrombosisThrombosis


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Vascular DefectsVascular DefectsVascular Defects

!Hereditary vascular purpurasHereditary connective tissue diseases

Hereditary vascular malformations

!Acquired vascular purpuras

Age-related vascular purpuraMechanical purpuras

Vitamin C deficiency (Scurvy)

Vasculitis/infection

Henoch-Schonlein purpura

Miscellaneous diseases

!! Hereditary vascular purpurasHereditary vascular purpurasHereditary connective tissue diseasesHereditary connective tissue diseases

Hereditary vascular malformationsHereditary vascular malformations

!! Acquired vascular purpurasAcquired vascular purpuras

Age-related vascular purpuraAge-related vascular purpuraMechanical purpurasMechanical purpuras

Vitamin C deficiency (Scurvy)Vitamin C deficiency (Scurvy)

Vasculitis/infectionVasculitis/infection

Henoch-Schonlein purpuraHenoch-Schonlein purpura

Miscellaneous diseasesMiscellaneous diseases


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Platelet DiseasesPlatelet DiseasesPlatelet Diseases

Platelet productionShortened survivalDefective adhesion

Defective aggregationDefective activation

Antiplatelet antibodies

Platelet productionShortened survivalDefective adhesion

Defective aggregationDefective activation

Antiplatelet antibodies

Hyperactive plateletsExcess activation

Hyperactive plateletsExcess activation

BleedingBleeding ThrombosisThrombosis


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Diseases of CoagulationDiseases of CoagulationDiseases of Coagulation

! Inherited diseases

von Willebrands disease

Factor deficiencies

! Acquired diseases

Disseminated intravascular coagulationCaogulation inhibitors

Vitamin K deficiency

Drug-induced hemorrhageDysproteinemias

Bleeding after cardiopulmonary bypass

!! Inherited diseasesInherited diseases

von Willebrands diseasevon Willebrands disease

Factor deficienciesFactor deficiencies

!! Acquired diseasesAcquired diseases

Disseminated intravascular coagulationDisseminated intravascular coagulationCaogulation inhibitorsCaogulation inhibitors

Vitamin K deficiencyVitamin K deficiency

Drug-induced hemorrhageDrug-induced hemorrhageDysproteinemiasDysproteinemias

Bleeding after cardiopulmonary bypassBleeding after cardiopulmonary bypass


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q

q qq

q

q

q

q

q

Factor

I

Factor

II

FactorV

FactorV

II

FactorVIII

FactorIX

FactorX

FactorX

I

FactorX

II

vWF:RCoF

vWF:A

g

Prekallikrein

HMWK

0

20

40

60

80

100

120

140

160

180

200

Fact

orActivity(%

)


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Platelet membranePlatelet membrane

GPIIbIIIaGPIIbIIIaGPIbGPIb

Adhesion siteAdhesion siteAggregation, vWF, andfibrinogen binding site

Aggregation, vWF, andfibrinogen binding site

vWFvWF VIII:CVIII:C

Subendothelial collagenSubendothelial collagen

PLT

Function

PLT

Function


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Platelet membrane

GPIIbIIIaGPIb

Adhesion siteAggregation, vWF, andfibrinogen binding site

vWF VIII:C

Subendothelial

collagen

vWDvWD


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Worldwide

Prevalence ofvWD is 1-3%

WorldwideWorldwide

Prevalence ofPrevalence ofvWD is 1-3%vWD is 1-3%


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History of vWDHistory of vWDHistory of vWD

! 1926 - Erik Adolf von Willebrand

described family with bleeding disorder

! Swedish island of Foglo in Alandarchipelago

! Termed hereditary pseudohemophilia! 1953 - Deficiency of plasma protein

distinct from factor VIII

! Multiple clinical variants discovered

! Most common congenital hemostaticdisorder

!! 1926 - Erik Adolf von Willebrand1926 - Erik Adolf von Willebrand

described family with bleeding disorderdescribed family with bleeding disorder!! Swedish island of Foglo in AlandSwedish island of Foglo in Aland

archipelagoarchipelago

!!

Termed hereditary pseudohemophiliaTermed hereditary pseudohemophilia!! 1953 - Deficiency of plasma protein1953 - Deficiency of plasma protein

distinct from factor VIIIdistinct from factor VIII

!! Multiple clinical variants discoveredMultiple clinical variants discovered

!! Most common congenital hemostaticMost common congenital hemostaticdisorderdisorder


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von Willebrands DiseaseClinical Features

von Willebrands Diseasevon Willebrands DiseaseClinical FeaturesClinical Features

! Common hereditary procoagulant disease! Frequently mild, most cases undiagnosed

! Multiple clinical variants

! Easy brusising very common

! Mucosal bleeding (epistaxis, GI bleeding,menorrhagia) very common

! Prolonged bleeding after surgery or trauma

! Bleeding caused by drugs affecting platelet

function! No history of hemarthroses or intramuscular

hematomas

!! Common hereditary procoagulant diseaseCommon hereditary procoagulant disease!! Frequently mild, most cases undiagnosedFrequently mild, most cases undiagnosed

!! Multiple clinical variantsMultiple clinical variants

!! Easy brusising very commonEasy brusising very common

!! Mucosal bleeding (epistaxis, GI bleeding,Mucosal bleeding (epistaxis, GI bleeding,menorrhagia) very commonmenorrhagia) very common

!! Prolonged bleeding after surgery or traumaProlonged bleeding after surgery or trauma

!! Bleeding caused by drugs affecting plateletBleeding caused by drugs affecting platelet

functionfunction!! No history of hemarthroses or intramuscularNo history of hemarthroses or intramuscular

hematomashematomas


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ClinicalFeaturesof vWD

ClinicalClinicalFeaturesFeaturesof vWDof vWD

Easy Bruising

GI Bleeding

Menorrhagia

Epistaxis

Prolonged

bleeding after

trauma

Drug-Induced

Bleeding


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Relationship Between vWFand ABO Blood Groups

Relationship Between vWFRelationship Between vWFand ABO Blood Groupsand ABO Blood Groups

Individuals withBlood Group O have

significantly lowerlevels of vWF thanthose with blood

groups A, B, or AB

Individuals withBlood Group O have

significantly lowerlevels of vWF thanthose with blood

groups A, B, or AB


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von Willebrands DiseaseClassification

von Willebrands Diseasevon Willebrands DiseaseClassificationClassification

! Type 1 - 70-80%, mild, autosomal recessive

! Type 2

Type 2A - 15-20%, mild

Type 2N - Rare, moderate, failure of vWF tocomplex with VIII:C

Type 2B - Rare, thrombocytopenia,increased vWF affinity for PLTS

! Type 3 - Very rare, severe, decreased vWF andfactor VIII, autosomal recessive

! Platelet-Type Pseudo vWF - Abnormality of PLTGP1b receptor, increased vWF affinity,resembles Type 2B

! Acquired vWF - Usually autoimmune etiology

!! Type 1 - 70-80%, mild, autosomal recessiveType 1 - 70-80%, mild, autosomal recessive

!! Type 2Type 2

Type 2A - 15-20%, mildType 2A - 15-20%, mild

Type 2N - Rare, moderate, failure of vWF toType 2N - Rare, moderate, failure of vWF tocomplex with VIII:Ccomplex with VIII:C

Type 2B - Rare, thrombocytopenia,Type 2B - Rare, thrombocytopenia,increased vWF affinity for PLTSincreased vWF affinity for PLTS

!! Type 3 - Very rare, severe, decreased vWF andType 3 - Very rare, severe, decreased vWF andfactor VIII, autosomal recessivefactor VIII, autosomal recessive

!! Platelet-Type Pseudo vWF - Abnormality of PLTPlatelet-Type Pseudo vWF - Abnormality of PLTGP1b receptor, increased vWF affinity,GP1b receptor, increased vWF affinity,resembles Type 2Bresembles Type 2B

!! Acquired vWF - Usually autoimmune etiologyAcquired vWF - Usually autoimmune etiology


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von Willebrands DiseaseLaboratory Features

von Willebrands Diseasevon Willebrands DiseaseLaboratory FeaturesLaboratory Features

! Normal PLT (with exceptions)! Prolonged bleeding time! Prolonged aPTT! Decreased factor VIII activity

(FVIII:C)! Decreased vWF antigen

(vWF:Ag)! Abnormal ristocetin cofactor

activity (vWF:RCoF)! Abnormal vWF multimeric

composition! Molecular abnormalities

!! Normal PLT (with exceptions)Normal PLT (with exceptions)

!! Prolonged bleeding timeProlonged bleeding time

!! Prolonged aPTTProlonged aPTT

!! Decreased factor VIII activityDecreased factor VIII activity(FVIII:C)(FVIII:C)

!! Decreased vWF antigenDecreased vWF antigen(vWF:Ag)(vWF:Ag)

!! Abnormal ristocetin cofactorAbnormal ristocetin cofactoractivity (vWF:RCoF)activity (vWF:RCoF)

!! Abnormal vWF multimericAbnormal vWF multimericcompositioncomposition

!! Molecular abnormalitiesMolecular abnormalities


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Diagnostic Assays for vWD IDiagnostic Assays for vWD IDiagnostic Assays for vWD I

! Factor VIII activity

Clotting assay

Capacity of patient plasma dilutions to correctclotting time of FVIII-deficient plasma

! vWF Activity (RCoF Activity)

Platelet aggregation assay

Different concentrations of ristocetin mixed withpatient PPP and normal platelets

! vWF Antigen

Immunoassay quantitation

ELISA commonly utiized

!! Factor VIII activityFactor VIII activity

Clotting assayClotting assay

Capacity of patient plasma dilutions to correctCapacity of patient plasma dilutions to correct

clotting time of FVIII-deficient plasmaclotting time of FVIII-deficient plasma

!! vWF Activity (RCoF Activity)vWF Activity (RCoF Activity)

Platelet aggregation assayPlatelet aggregation assay

Different concentrations of ristocetin mixed withDifferent concentrations of ristocetin mixed with

patient PPP and normal plateletspatient PPP and normal platelets

!! vWF AntigenvWF Antigen

Immunoassay quantitationImmunoassay quantitation

ELISA commonly utiizedELISA commonly utiized


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Diagnostic Assays for vWD IIDiagnostic Assays for vWD IIDiagnostic Assays for vWD II

! Ristocetin-induced agglutination assay

Platelet aggregation assay

Patient PRP + graded ristocetin concentrations

! Cryoprecipitate-inducedagglutinationassayPatient PRP + normal cryoprecipitate

Spontaneous agglutination with platelet-typepseudo-vWD

! vWF multimer analysis

Gel electrophoresis

Subtypes show different migration patternsUsed to subtype vWD after Dx established

Laborious and expensive

!! Ristocetin-induced agglutination assayRistocetin-induced agglutination assay

Platelet aggregation assayPlatelet aggregation assayPatient PRP + graded ristocetin concentrationsPatient PRP + graded ristocetin concentrations

!! Cryoprecipitate-inducedCryoprecipitate-inducedagglutinationagglutinationassayassayPatient PRP + normal cryoprecipitatePatient PRP + normal cryoprecipitate

Spontaneous agglutination with platelet-typeSpontaneous agglutination with platelet-typepseudo-vWDpseudo-vWD

!! vWF multimer analysisvWF multimer analysis

Gel electrophoresisGel electrophoresis

Subtypes show different migration patternsSubtypes show different migration patternsUsed to subtype vWD after Dx establishedUsed to subtype vWD after Dx established

Laborious and expensiveLaborious and expensive


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vWF MultimersvWF MultimersvWF Multimers

Large

Multimers

Large

Multimers

Intermediate

Multimers

Intermediate

Multimers

Small

Multimers

Small

Multimers

NormalNormal Type IType I Type IIAType IIA Type IIBType IIB Type IIIType III


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vWF TreatmentvWF TreatmentvWF Treatment! Replacement therapy

Plasma derived factor VIII concentrates

Type 3, type 2B, type 2NFactor VIII concentrates, cryoprecipitate

Platelets

Platelet-type pseudo-vWD

Plasma concentrates contraindicated! Desmopressin acetate

Synthetic analog of vasopressin

Stimulates vWF and factor VIII release

Mainstay of Rx for Type I and Type 2A

Injection and nasal spray

! Ancillary therapyFibrinolytic inhibitors and fibrin glue

!! Replacement therapyReplacement therapy

Plasma derived factor VIII concentratesPlasma derived factor VIII concentrates

Type 3, type 2B, type 2NType 3, type 2B, type 2NFactor VIII concentrates, cryoprecipitateFactor VIII concentrates, cryoprecipitate

PlateletsPlatelets

Platelet-type pseudo-vWDPlatelet-type pseudo-vWD

Plasma concentrates contraindicatedPlasma concentrates contraindicated!! Desmopressin acetateDesmopressin acetate

Synthetic analog of vasopressinSynthetic analog of vasopressin

Stimulates vWF and factor VIII releaseStimulates vWF and factor VIII release

Mainstay of Rx for Type I and Type 2AMainstay of Rx for Type I and Type 2A

Injection and nasal sprayInjection and nasal spray

!! Ancillary therapyAncillary therapy

Fibrinolytic inhibitors and fibrin glueFibrinolytic inhibitors and fibrin glue


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Case Studiesin

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Case #1The EndCase #1Case #1The EndThe End

case 01 plate let disorders

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