Atherothrombosis Pathophysiology

What Is Atherothrombosis?

• The formation of a thrombus on an existing atherosclerotic plaque

• Atherothrombosis is a new term recognizing that atherosclerosis (plaque development) and acute thrombosis are integrally related to the presentation of vascular events

• A generalized progressive disease of large- and mid-size arteries that affects multiple vascular beds, including cerebral, coronary, and peripheral arteries

• The underlying disease leading to myocardial infarction (MI), peripheral arterial disease (PAD), ischemia and many forms of stroke

MI, myocardial infarction; PAD, peripheral artery disease.Fuster V, et al. Vasc Med. 1998;3:231-239.Rauch U, et al. Ann Intern Med. 2001;134:122-238.

Atherothrombosis* is theLeading Cause of Death Worldwide1

* Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.1 The World Health Report 2001. Geneva. WHO. 2001.

22.3

19.3

12.6

9.7

9

6.3

0 5 10 15 20 25 30

Atherothrombosis*

Infectious Disease

Cancer

Injuries

Pulmonary Disease

AIDS

Causes of Mortality (%)

Atherothrombosis Significantly Shortens Life

Analysis of data from the Framingham Heart Study.Peeters A, et al. Eur Heart J. 2002;23:458-466.

Atherothrombosis reduces life expectancy by around 8-12 years in patients aged over 60 years1

Average Remaining Life Expectancy at Age 60 (Men)

0

4

8

12

16

20

Healthy

Yea

rs

History of AMI

-9.2 years

History of Cardiovascular Disease

-7.4 years

History of Stroke

-12 years

3.2 Million Hospital Admissions

Coronary Atherosclerosis

Acute Myocardial Infarction

1,153,000 Admissions

829,000 Admissions

Hospitalizations in the USDue to Vascular Disease

Cerebrovascular Disease

961,000 Admissions

Vascular Disease

Other IschemicHeart Disease

280,000 Admissions

Popovic JR, Hall MJ. Advance Data. 2001;319:1-20.

Preventable Deaths

Approximately 57,000 deaths could be avoided each year in the US if patients were given appropriate care.

National Committee for Quality Assurance. Washington, DC 2003.

700Cervical-cancer screening

Prenatal care

-blocker treatment

Breast-cancer screening

Smoking cessation

Cholesterol management

Diabetes care

High-blood pressure control

1500

1700

2500

2700

6500

13,600

28,300

* Based on data from the ARIC study of the National Heart, Lung, and Blood Institute, 1987-1994. Includes Americans hospitalized with definite or probable MI or fatal CHD, not including silent MIs. ACS, acute coronary syndrome; MI, myocardial infarction; ARIC, Atherosclerotic Risk in Communities,

CHD, coronary heart disease. American Heart Association. Heart Disease and Stroke Statistics—2003 Update.

Epidemiology of ACS in the United States

• Single largest cause of death• 515,204 US deaths in 2000• 1 in every 5 US deaths

• Incidence• 1,100,000 Americans will have a new or recurrent

coronary attack each year and about 45% will die*• 550,000 new cases of angina per year

• Prevalence• 12,900,000 with a history of MI, angina, or both

Epidemiology of Stroke in the United States

• Prevalence

• 4.7 million cases

• Incidence

• 700,000 new or recurrent strokes each year

• Morbidity/mortality

• Third leading cause of death

• 1 of every 14 deaths (168,000 deaths)

• Stroke: a leading cause of long-term disability

American Heart Association. Heart Disease and Stroke Statistics—2003 Update.

Peripheral Arterial Disease

• PAD affects 12% of the adult population1,2

• 20% of the population aged >70

• Associated with 6-fold increase in CV mortality3

• Underrecognized and undertreated4

• Measurement simple, inexpensive, and noninvasive

• Appropriate for risk assessment and screening

• Patients at high risk need aggressive risk-factor modification and antiplatelet drugs4

PAD, peripheral artery disease; CV, cardiovascular.1 Nicolaides AN. Symposium. Nov. 1997. 2 Hiatt WR, et al. Circulation. 1995; 91:1472-1479.3 Criqui MH, et al. N Engl J Med. 1992; 326:381-386. 4 Hirsch AT, et al. JAMA. 2001;286:1317-1324.

CerebralIschemic stroke

Transient ischemic attack

CardiacMyocardial infarction

Angina pectoris (stable, unstable)

Peripheral Arterial Disease Critical limb ischemia, claudication

Clinical Manifestations of Atherothrombosis

Overlap of Vascular Disease in Patients With Atherothrombosis

PAD, peripheral artery disease.Adapted from TransAtlantic Inter-Society Consensus Group. J Vasc Surg. 2000;31:S16.

Coronary Disease

PAD

12%

33%15%

5% 14%

13%

8%

Cerebral Disease

Coronary Disease

PAD

19%

30%25%

4% 12%

7%

3%

Cerebral Disease

CAPRIE Aronow & Ahn

Common Underlying Atherothrombotic Disease Process

MI, myocardial infarction; PAD, peripheral arterial disease; CV, cardiovascular.Ness J, et al. J Am Geriatr Soc. 1999;47:1255-1256. Schafer AI. Am J Med. 1996;101:199-209.

Atherothrombotic Events (MI, Stroke, or CV Death)

Plaque Rupture

Platelet Adhesion,

Activation, and Aggregation

Thrombus Formation

MIAtherothromboti

c Stroke PADUnstable Angina

Risk of a Second Atherothrombotic EventIncreased Risk vs General Population (%)

Original Event MI Stroke

MI 5-7 timesgreater risk

(includes death)*

3-4 timesgreater risk

(includes TIA)

Stroke 2-3 timesgreater risk

(includes angina and sudden death)*

9 timesgreater risk

PAD 4 timesgreater risk*

2-3 timesgreater risk

(includes TIA)

* Death documented within 1 hour of an event attributed to CHD.Note:This chart is based on epidemiologic data and is not intended to provide a direct basis for

comparison of risks between event categories. MI, myocardial infarction; TIA, transient aschemic attack, PAD, peripheral artery disease.Adult Treatment Panel II. Circulation. 1994;89:1333-1363.Kannel, WB. J Cardiovasc Risk. 1994;1:333-339.Wilterdink, JI, et al. Arch Neurol. 1992;49:857-863. Crique, MH, et al. N Engl J Med. 1992;326:381-386.

UnstableanginaMI

Ischemic stroke/TIA

Critical legischemia

Intermitentclaudication

CV death

ACS

Atherosclerosis

Stable angina/ Intermittent claudication

Atherothrombosis: A Generalized and Progressive Process

Thrombosis

Adapted from Libby P. Circulation. 2001;104:365-372.

Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque

Adapted from Falk E, et al. Circulation. 1995;92:657-671.

Characteristics of Unstable and Stable Plaque

Thin fibrous cap

Inflammatory cells

FewSMCs

Erodedendothelium

Activatedmacrophages

Thickfibrous cap

Lack ofinflammatory cells

Foam cells

Intactendothelium

MoreSMCs

Libby P. Circulation. 1995;91:2844-2850.

Unstable Stable

Plaque Rupture

Andrew Farb, MD by permission.

Risk Factors for Plaque Rupture

Impaired Fibrinolysis

FibrinogenDiabetesMellitus

Cholesterol

SmokingCap Fatigue

Atheromatous Core(size/consistency)

Cap Inflammation

Systemic FactorsLocal Factors

Homocysteine

PlaqueRupture

Fuster V, et al. N Engl J Med. 1992;326:310-318.Falk E, et al. Circulation. 1995:92:657-671.

Cap Thickness/

Consistency

Multiple Risk Factors for Atherothrombosis

MI, myocardial infarction.Adapted from Yusuf S, et al. Circulation. 2001;104:2746-2753.Drouet L. Cerebrovasc Dis. 2002;13(suppl 1):1-6.

Lifestyle• Smoking• Diet• Lack of exercise

Genetic Traits• Gender• PlA2

GeneralizedDisorders• Age• Obesity

SystemicConditions• Hypertension• Hyperlipidemia• Diabetes• Hypercoagulable

states• Homocysteinemia

Atherothrombotic Manifestations

(MI, stroke, vascular death)

Inflammation• Elevated CRP• CD40 Ligand, IL-6 • Prothrombotic factors (F I and II)• Fibrinogen

Local Factors• Blood flow patterns• Shear stress• Vessel diameter• Arterial wall structure• % arterial stenosis

Risk Factors for Ischemic Stroke

Modifiable• Hypertension

• Atrial fibrillation

• Cigarette smoking

• Hyperlipidemia

• Alcohol abuse

• Carotid stenosis

• Physical inactivity

• Obesity

• Diabetes

Nonmodifiable• Age

• Sex

• Race/Ethnicity

• Heredity

RCA WallLAD Wall

Eccentric (“lipid-rich”) Concentric (“fibrotic”) Ectatic (“remodeled”)

Black-Blood Coronary Plaque MR

MR, magnetic resonance; LAD, left anterior descending; RCA, right coronary artery.Fayad ZA, et al. Circulation. 2000;102:506-510. (with permission)

LAD Wall

Evidence of Multiple “Vulnerable” Plaques in ACS

ACS, acute coronary syndrome.Asakura M, et al. J Am Coll Cardiol. 2001;37:1284-1288. (with permission)

Angiographic & angioscopic images in 58-year-old man with anterior myocardial infarction

Multiple “vulnerable”

plaques detected in non-culprit

segments 10-12

Culprit lesion (#8)detected with

thrombus (red)

Multiple “vulnerable”

plaques detected in non-culprit segments 1-7

Multiple Complex Coronary Plaques in Patients With Acute MI

MI, myocardial infarction.Goldstein JA, et al. N Eng J Med. 2000;343:915-922. (with permission)

Culprit lesionCulprit lesion

Multiple plaquesdetected

Multiple plaquesdetected

Multiple plaquesdetected

Multiple plaquesdetected

ACS, acute coronary syndrome.Rioufol G, et al. Circulation 2002;106:804-808. (with permission)

Frequency of multiple active plaque ruptures beyond the culprit lesion

Pat

ien

ts (

%)

80% of Patients With 2 Plaques

0

5

10

15

20

25

30

0 1 2 3 4 5

N=24

Frequency of Multiple “Active” Plaques in Patients With ACS

ACS: Tip of the Atherothrombotic “Iceberg”

ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction. Adapted from Goldstein JA. J Am Coll Cardiol. 2002;39:1464-1467.

Presence of Multiple Coronary Plaques

Vascular Inflammation

Persistent Hyperreactive Platelets

Clinical

Subclinical

Acute Plaque Rupture ACS (UA/NSTEMI/STEMI)

Hemostatic Plug Formation

ThrombinThrombin

AGGREGATION

FibrinFibrin

HemostaticHemostaticClotClot

ClottingClottingPlatelet AggregationPlatelet Aggregation

0 min0 min 10 min10 min5 min5 min

SECONDARYSECONDARY

PRIMARYPRIMARY

COAGULATION

Adapted from Ferguson JJ, et al. Antiplatelet Therapy in Clinical Practice. 2000:15-35.

GP IIb/IIIa InhibitorsGP IIb/IIIa Inhibitors

1. Platelet Adhesion

2. Platelet Activation

Platelet

GP Ib

Plaque rupture Activated Platelet

GP IIb/IIIa 3. Platelet AggregationASA,

Clopidogrel/Ticlopidine

ASA, Clopidogrel/Ticlopidine

ASA, acetylsalicyclic acid.Cannon and Braunwald, Heart Disease. 2001.

TxA2

Fibrinogen

Platelets Role in Thrombosis

Fibrin PlateletsRBCs

White Thrombus

Fibrin PlateletsRBCs

Coagulation Thrombus

High Flow Slow Flow

Platelets: Role in Thrombosis

RBCs, red blood cells.

ThrombinSerotoninEpinephrineCollagen

ADPADP

Activation

TXATXA22

ActivatedPlatelet

COXCOX

Degranulation

Aspirin

Gp Gp IIb/IIIa fibrinogenfibrinogenreceptorreceptor

To neighboringTo neighboringplateletplatelet

Clopidogrel

Ticlopidine

Platelet agonistsADPATPserotonincalciummagnesium

Adhesive proteins

thrombospondinfibrinogenp-selectinvWF

Coagulation factors

factor Vfactor XIPAI-1

Inflammatory factors

platelet factor 4CD 154 (CD 40 ligand)PDGF

IV Gp IIb/IIIaInhibitors

TXA, thromboxane; PDGF, platelet-derived growth factor.

Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes

Platelet Aggregability Status

0

10

20

30

40

50 Death

Cardiac Events

10.36.4

14.9

24.1

46.2

34.6

Pat

ien

ts (

%)

*RR=1.6(CI 0.5-5.5)

Negative(n=94)

*RR=1.6(CI 0.7-3.5)

*RR=5.4(CI 2.2-13.4)

*RR=3.1(CI 1.6-5.8)

Intermediate(n=29)

Positive(n=26)

ACS, acute coronary syndrome.* Relative risk compared to group with negative aggregation.

Adapted from Trip MD, et al. N Engl J Med. 1990;322:1549-1554.

Platelets Release Inflammatory Mediators and Lead to Vascular Inflammation and Plaque Instability

RANTES (Regulated on Activation, Normal T-cellExpressed and Secreted).Libby P, et al. Circulation. 2001;103:1718-1720.

Inflammatory Modulators• CD 40 ligand• Platelet factor 4• RANTES

Unstable Plaque

ActivatedPlatelets

PlaqueRupture &

Thrombosis

• Thrombospondin• Platelet-derived growth factor• Nitric oxide

CD40L is activated by agonists such as ADP, thrombin, or collagen. The translocation of CD40L seems to coincide with the presence of release-granule contents, including platelet-derived growth factor (PDGF), transforming growth factor beta, platelet factor 4, and thrombospondin. GP IIb/IIIa antagonists block the hydrolysis and subsequent release of SCD40L from platelets.

The Shedding of Soluble SCD40L During Platelet Stimulation

SCD40L, SCD40 ligand; PDGF, platelet-derived growth factor; TGF-, transforming growth factor-beta; PF4, platelet factor 4; TSP,thrombospondin.Andre P, et al. Circulation. 2002:106:896-899. (with permission)

ADPThrombinCollagen

CD4OL

sCD4OL GP IIb-IIIa

Antagonists

• PDGF• TGF• PF4• TSP

Inflammatory Modulators Produced by Platelets

TGF-ß5

Stimulate smooth muscle cell biosynthesis

Nitric oxide3

Effects on monocyte, leucocyte, endothelium, and smooth muscle cells

CD154 (CD40 ligand)1,4

Regulates macrophage and smooth muscle cell functions

RANTES2

Influences macrophage adhesion to endothelial cell

PF41

Mediates shear-resistant arrest of monocytes to endothelium

Platelet

PDGF1 Induces proliferation of

smooth muscle cells

Thrombospondin1

Interacts with cell surface receptors

1 Libby P, et al. Circulation. 2001;103:1718-1720. 2 von Hundelshausen P, et al. Circulation. 2001;103:1772-1777. 3 Wever RMF, et al. Circulation. 1998;97:108-112. 4 Hermann A, et al. Platelets. 2001;12:74-82. 5 Robbie L, et al. Ann N Y Acad Sci. 2001; 947:167-79.

The Detrimental Role of Platelet-Derived sCD40Ligand in Cardiovascular Disease

Adapted from Andre P, et al. Circulation. 2002:106:896-899.

Inflammation– induces production/release

of pro-inflammatory cytokines from vascular and atheroma cells

Thrombosis – stabilizes platelet-rich

thrombi

Restenosis – prevents reendothelialization

of the injured vessel – contributes to activation

and proliferation of smooth muscle cells

Heeschen C, et al. N Engl J Med. 2003;348:1104-1111. (with permission)

Association Between Soluble CD40 Ligand Levels and the Rate of Cardiac Events

0

5

10

15

20

24 h 72 h 30 d 6 mo

1st quintile

2nd quintile

3rd quintile

4th quintile

5th quintile

Time

Dea

th o

r N

on

fata

l M

yoca

rdia

l In

farc

tio

n (

%)

P=.13

P=.003

P=.004

P<.001

0 15 30 45 60 750

2

4

6

8

10

Monocyte–Platelet Aggregates (%)

So

lub

le C

D40

Lig

and

(g

/Lit

er)

r =0.75P<.001

Level Of Soluble CD40 Ligand and Monocyte—Platelet Activation in 161 Patients With Chest Pain

Heeschen C, et al. N Engl J Med. 2003:348:1104-1111. (with permission)

Heeschen C, et al. N Engl J Med. 2003;348:1104-1111.

Dea

t h o

r N

on

fata

l Myo

card

ial

Inf a

rcti

on

(%

)

Kaplan-Meier Curves Showing Cumulative Incidence of Death or Nonfatal Myocardial Infarction

0

5

10

15

20

0 1 2 3 4 5 6

Follow-up (mo)

High level, placebo

Low level, placebo

High level, abciximab

Low level, abciximab