Pathology 430/826

Thrombosis

David Lillicrap

Cardiovascular Disease30% of all deaths in Canada

54% ischemic heart disease

20% stroke

23% heart attack

Arterial Thrombosis

Myocardial Infarction

Cerebral Infarction following Cerebrovascular Thrombosis

Peripheral Vascular Disease

Deep Vein Thrombosis

30% Progression to Pulmonary Embolism

Dr. Rudolph Virchow1821-1902

AbnormalBlood Flow

AbnormalVessel Wall

AbnormalBlood

The Hypercoagulable State(thrombophilia)

HemophiliaSingle Gene Mutation

Thrombosis Multigenic + Environmental

Factors

Pathogenetic Associations and Hemostasis

Genetic diagnosisavailable

Genetic therapyfeasible

Genetic pathogenesisstill under investigation

Multifactorial,Complex

PathogenesisSimple,

MonogenicPathology

90% of Canadians have at least one risk factor for heart disease or stroke

• Smoking• Alcohol• Lack of physical activity• Obesity• Hypertension• Hypercholesterolemia• diabetes

Venous Thromboembolism

Incidence

5 cases per 100,000 person/year (<15 years old)

5 cases per 1,000 person/year(80 years old)

Influence of Age on the Incidence of Venous Thromboembolism

Types of Thrombosis

Arterial: platelet-based (white) thrombus

Platelet-VWF interactions criticalAssociated with end-stage atherosclerosis

Venous: Fibrin-based (red) thrombus

Coagulation factors critical

Venous stasis

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Blood flow

Physiological Hemostatic Mechanism

FibrinInsoluble end product

Common pathway

Extrinsic pathway Intrinsic pathway1

3

2

Coagulation System

1

3

2

collagen

collagencollagencollagen

Blood Flow

collagencollagen

collagen

collagen collagencollagen

Blood Flow

collagencollagen

VWFVWF VWF VWF

VWFSubendothelial Tissue Factor

Microparticle Tissue Factor

(WBC/platelet derived)

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Platelet adhesionGpIb/VWF

Blood Flow

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Platelet adhesionGpIb/VWF

Blood Flow

Platelet RollingGpIb/VWFGpVI +21/collagen

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Platelet adhesionGpIb/VWF

Blood Flow

Platelet RollingGpIb/VWFGpVI +21/collagen

Stable adhesionplatelet activation aggregationGpIIb/IIIa – fibrinogen/VWF

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Blood flow

Physiological Hemostatic Mechanism

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Occlusive Platelet Thrombus

Coagulation System

1

3

2

VWF

VWF

VWF

VWF VWF VWFcollagen

collagencollagen

collagen

Occlusive Platelet Thrombus + Fibrin

Mechanisms to Control Thrombus Development

1. Endothelial Cell “protection”

Prostacyclin(PGI2)

VasodilatationInhibits platelet aggregation

Cell surface Heparin-like molecules

Cell surface ADPase

Endothelial Cell

Mechanisms to Control Thrombus Development

2. VWF degradation

Globular formof VWF

Normal plasmaconformation

Growing thrombus = Vasoconstriction = Increased shear

Extended form of VWF

ADAMTS13 accessible

(mechano-enzymatic cleavage)

Mechanisms to Control Thrombus Development

3. Anticoagulant plasma proteins

- antithrombin- protein C- protein S- tissue factor pathway inhibitor (TFPI)

ThrombinIIa

Thrombomodulin

Endothelial Cell

Protein C Activated Protein C

FVIIIa

FVa

Protein S

EPCR

+vefeedback

AntithrombinAnticoagulation

+vefeedback

TFPIAnticoagulation

Mechanisms to Control Thrombus Development

4. Fibrinolytic pathway

– plasmin-mediated degradation of fibrin

Endothelial Cell

Tissue Plasminogen Activator (tPA)

Plasminogen

Plasmin

FibrinDegradation

Thrombotic Risk Factors

1. Inherited

a) Frequent - minor influence

b) Rare – more significant effect

2. Acquired

Inherited Thrombotic Risk Factors - Thrombophilic Traits

Prevalence: 2-5% of Western Populations

a) Factor V Leiden - inability to proteolytically inactivate FVa

b) Prothrombin gene varaint – enhanced stability of prothrombin mRNA

Enhanced thrombotic risk: 2 to 7-fold increase

Inherited Thrombotic Risk Factors - Thrombophilic Traits

Prevalence: <1:1,000

a) Antithrombin deficiency

b) Protein C deficiency

c)Protein S deficiency

Enhanced thrombotic risk: 5 to 20-fold increase

Acquired Thrombotic Risk Factors

• Smoking• Lack of physical activity• Obesity• Hypertension• Hypercholesterolemia• Diabetes• Cancer• Inflammation/infection• Pregnancy/estragenic states

Pathological Thrombotic Events – Very Often Multifactorial

1. 32 year old female long distance runner - DVT + PE

Ruptured synovial cyst in knee + dehydration.

2. 43 year old female - large DVT

chronic crohns disease + Factor V Leiden heterozygote

3. 35 year old female – large iliac vein thrombosis

pregnancy + antithrombin deficiency

Break