Cardiovascular Disease30% of all deaths in Canada
54% ischemic heart disease
20% stroke
23% heart attack
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)
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
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
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
Prostacyclin(PGI2)
VasodilatationInhibits platelet aggregation
Cell surface Heparin-like molecules
Cell surface ADPase
Endothelial Cell
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)
Mechanisms to Control Thrombus Development
4. Fibrinolytic pathway
– plasmin-mediated degradation of fibrin
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
Top Related