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Atherothrombosis Pathophysiology. What Is Atherothrombosis?. The formation of a thrombus on an existing atherosclerotic plaque

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What is atherothrombosis
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 the leading cause of death worldwide 1
Atherothrombosis* is theLeading Cause of Death Worldwide1

6.3

Pulmonary Disease

Injuries

9

AIDS

9.7

Cancer

12.6

19.3

Infectious Disease

22.3

Atherothrombosis*

0

5

10

15

20

25

30

Causes of Mortality (%)

* Atherothrombosis defined as ischemic heart disease and cerebrovascular disease.

1 The World Health Report 2001. Geneva. WHO. 2001.


Atherothrombosis significantly shortens life
Atherothrombosis Significantly Shortens Life

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

Average Remaining Life Expectancy at Age 60 (Men)

20

-7.4 years

16

-9.2 years

-12 years

12

Years

8

4

0

Healthy

History of

Cardiovascular Disease

History of AMI

History of Stroke

Analysis of data from the Framingham Heart Study.

Peeters A, et al. Eur Heart J. 2002;23:458-466.


Hospitalizations in the us due to vascular disease
Hospitalizations in the USDue to Vascular Disease

Vascular Disease

3.2 Million Hospital Admissions

Cerebrovascular Disease

Coronary

Atherosclerosis

Acute Myocardial Infarction

Other IschemicHeart Disease

961,000 Admissions

1,153,000

Admissions

829,000 Admissions

280,000 Admissions

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


Preventable deaths

28,300

13,600

6500

2700

2500

1700

1500

700

Preventable Deaths

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

High-blood pressure control

Diabetes care

Cholesterol management

Smoking cessation

Breast-cancer screening

-blocker treatment

Prenatal care

Cervical-cancer screening

National Committee for Quality Assurance. Washington, DC 2003.


Epidemiology of acs in the united states
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

* 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 stroke in the united states
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
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.


Clinical manifestations of atherothrombosis
Clinical Manifestations of Atherothrombosis

  • Cerebral

    Ischemic stroke

    Transient ischemic attack

  • Cardiac

    Myocardial infarction

    Angina pectoris (stable, unstable)

    Peripheral Arterial Disease

    Critical limb ischemia, claudication


Overlap of Vascular Disease in Patients With Atherothrombosis

CAPRIE

Aronow & Ahn

Cerebral Disease

Coronary Disease

Cerebral Disease

Coronary Disease

25%

7%

30%

15%

13%

33%

3%

8%

4%

12%

5%

14%

19%

12%

PAD

PAD

PAD, peripheral artery disease.

Adapted from TransAtlantic Inter-Society Consensus Group. J Vasc Surg. 2000;31:S16.


Common underlying atherothrombotic disease process
Common Underlying Atherothrombotic Disease Process

Atherothrombotic Stroke

Unstable Angina

MI

PAD

Platelet Adhesion, Activation, and Aggregation

Thrombus Formation

Plaque Rupture

Atherothrombotic Events (MI, Stroke, or CV Death)

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.


Risk of a second atherothrombotic event
Risk of a Second Atherothrombotic Event

* 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.


Atherothrombosis a generalized and progressive process
Atherothrombosis: A Generalized and Progressive Process

Thrombosis

UnstableanginaMI

Ischemic stroke/TIA

Critical legischemia

Intermitentclaudication

CV death

ACS

Atherosclerosis

Stable angina/ Intermittent claudication

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


Atherothrombosis thrombus superimposed on atherosclerotic plaque
Atherothrombosis: Thrombus Superimposed on Atherosclerotic Plaque

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


Characteristics of unstable and stable plaque
Characteristics of Unstable and PlaqueStable Plaque

Unstable

Stable

Lack ofinflammatory cells

Inflammatory cells

Thickfibrous cap

Thin fibrous cap

FewSMCs

MoreSMCs

Intactendothelium

Erodedendothelium

Activatedmacrophages

Foam cells

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


Plaque rupture
Plaque Rupture Plaque

Andrew Farb, MD by permission.


Risk factors for plaque rupture
Risk Factors for Plaque Rupture Plaque

Systemic Factors

Local Factors

  • Cap Fatigue

Smoking

Cholesterol

  • Atheromatous Core(size/consistency)

  • DiabetesMellitus

  • Fibrinogen

  • Cap Thickness/ Consistency

  • Homocysteine

  • Cap Inflammation

  • Impaired Fibrinolysis

PlaqueRupture

Fuster V, et al. N Engl J Med. 1992;326:310-318.

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


Multiple risk factors for atherothrombosis
Multiple Risk Factors for Atherothrombosis Plaque

  • Lifestyle

  • Smoking

  • Diet

  • Lack of exercise

  • Generalized

  • Disorders

  • Age

  • Obesity

  • Systemic

  • Conditions

  • Hypertension

  • Hyperlipidemia

  • Diabetes

  • Hypercoagulable states

  • Homocysteinemia

Atherothrombotic Manifestations

(MI, stroke, vascular death)

  • Genetic Traits

  • Gender

  • PlA2

  • 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

MI, myocardial infarction.

Adapted from Yusuf S, et al. Circulation. 2001;104:2746-2753.

Drouet L. Cerebrovasc Dis. 2002;13(suppl 1):1-6.


Risk factors for ischemic stroke

Modifiable Plaque

Hypertension

Atrial fibrillation

Cigarette smoking

Hyperlipidemia

Alcohol abuse

Carotid stenosis

Physical inactivity

Obesity

Diabetes

Nonmodifiable

Age

Sex

Race/Ethnicity

Heredity

Risk Factors for Ischemic Stroke


Black blood coronary plaque mr
Black-Blood Coronary Plaque MR Plaque

LAD Wall

RCA Wall

LAD Wall

Eccentric (“lipid-rich”)

Concentric (“fibrotic”)

Ectatic (“remodeled”)

MR, magnetic resonance; LAD, left anterior descending; RCA, right coronary artery.

Fayad ZA, et al. Circulation. 2000;102:506-510. (with permission)


Evidence of Multiple “Vulnerable” Plaques Plaquein ACS

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

Multiple “vulnerable”

plaques detected in non-culprit segments 1-7

Culprit lesion (#8)

detected with

thrombus (red)

Multiple “vulnerable”

plaques detected in

non-culprit segments 10-12

ACS, acute coronary syndrome.

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


Multiple complex coronary plaques in patients with acute mi
Multiple Complex Coronary Plaques in Patients With Acute MI Plaque

Multiple plaques

detected

Multiple plaques

detected

Culprit lesion

MI, myocardial infarction.

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


Frequency of Multiple “Active” Plaques in Patients With ACS

80% of Patients With  2 Plaques

N=24

Patients (%)

Frequency of multiple active plaque ruptures beyond the culprit lesion

ACS, acute coronary syndrome.

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


ACS: Tip of the Atherothrombotic “Iceberg” ACS

Acute Plaque Rupture ACS (UA/NSTEMI/STEMI)

Clinical

Subclinical

Persistent Hyperreactive

Platelets

Presence of Multiple

Coronary Plaques

Vascular

Inflammation

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.


Hemostatic plug formation
Hemostatic Plug Formation ACS

PRIMARY

AGGREGATION

Platelet Aggregation

Clotting

Hemostatic

Clot

Fibrin

SECONDARY

Thrombin

COAGULATION

0 min

10 min

5 min

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


Activated Platelet ACS

GP IIb/IIIa

Fibrinogen

Platelets Role in Thrombosis

1. Platelet Adhesion

Platelet

GP Ib

2. Platelet Activation

Plaque rupture

3. Platelet Aggregation

ASA,

Clopidogrel/Ticlopidine

TxA2

GP IIb/IIIa Inhibitors

ASA, acetylsalicyclic acid.

Cannon and Braunwald, Heart Disease. 2001.


Platelets role in thrombosis
Platelets: Role in Thrombosis ACS

High Flow Slow Flow

RBCs

Platelets

Fibrin

RBCs

Platelets

Fibrin

White Thrombus

Coagulation Thrombus

RBCs, red blood cells.


IV Gp IIb/IIIa ACS

Inhibitors

Aspirin

TXA2

ADP

Adhesive proteins

thrombospondin

fibrinogen

p-selectin

vWF

Platelet agonists

ADP

ATP

serotonin

calcium

magnesium

Coagulation factors

factor V

factor XI

PAI-1

Inflammatory factors

platelet factor 4

CD 154 (CD 40 ligand)

PDGF

Activated

Platelet

Clopidogrel

Ticlopidine

To neighboring

platelet

Gp IIb/IIIa

fibrinogen

receptor

Thrombin

Serotonin

Epinephrine

Collagen

COX

Activation

Degranulation

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


Platelet hyperreactivity following acs predicts 5 year outcomes
Platelet Hyperreactivity Following ACS Predicts 5-Year Outcomes

*RR=3.1

(CI 1.6-5.8)

Death

46.2

50

*RR=5.4

(CI 2.2-13.4)

Cardiac Events

40

34.6

*RR=1.6

(CI 0.7-3.5)

30

24.1

Patients (%)

*RR=1.6

(CI 0.5-5.5)

20

14.9

10.3

6.4

10

0

Negative

(n=94)

Intermediate

(n=29)

Positive

(n=26)

Platelet Aggregability Status

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

ActivatedPlatelets

  • Inflammatory Modulators

  • CD 40 ligand

  • Platelet factor 4

  • RANTES

  • Thrombospondin

  • Platelet-derived growth factor

  • Nitric oxide

PlaqueRupture & Thrombosis

Unstable Plaque

RANTES (Regulated on Activation, Normal T-cellExpressed and Secreted).

Libby P, et al. Circulation. 2001;103:1718-1720.


The shedding of soluble scd40l during platelet stimulation

CD4OL Outcomes

ADP

Thrombin

Collagen

  • PDGF

  • TGF

  • PF4

  • TSP

sCD4OL

GP IIb-IIIa

Antagonists

The Shedding of Soluble SCD40L During Platelet Stimulation

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.

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)


Inflammatory modulators produced by platelets
Inflammatory Modulators OutcomesProduced by Platelets

PF41

  • Mediates shear-resistant arrest of monocytes to endothelium

PDGF1

  • Induces proliferation of smooth muscle cells

CD154

(CD40 ligand)1,4

  • Regulates macrophage and smooth muscle cell functions

RANTES2

  • Influences macrophage adhesion to endothelial cell

Platelet

Thrombospondin1

  • Interacts with cell surface receptors

Nitric oxide3

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

TGF-ß5

  • Stimulate smooth muscle cell biosynthesis

1 Libby P, et al. Circulation. 2001;103:1718-1720. 2 von Hundelshausen P, etal. 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
The Detrimental Role of Platelet-Derived sCD40Ligand in Cardiovascular Disease

  • 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

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


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

P<.001

P=.004

P=.003

Death or Nonfatal Myocardial Infarction (%)

P=.13

Time

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


Level of soluble cd40 ligand and monocyte platelet activation in 161 patients with chest pain
Level Of Soluble CD40 Ligand and of Cardiac EventsMonocyte—Platelet Activation in 161 Patients With Chest Pain

10

8

6

Soluble CD40 Ligand (g/Liter)

4

2

r=0.75

P<.001

0

0

15

30

45

60

75

Monocyte–Platelet Aggregates (%)

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


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

High level, placebo

Death or Nonfatal Myocardial Infarction (%)

Low level, abciximab

High level, abciximab

Low level, placebo

Follow-up (mo)

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


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