PATHOLOGY OF BLOOD VESSELS

By Dr. Martins

1.NORMAL VESSELS

• 3 concentric layer; intima, media & adventitia. Intima; internal elastic lamina

Media;external elastic lamina

Adventitia; vasa vasorum

• Arteries; Elastic(large): aorta, innominate, subclavian,

Muscular(medium-sized): renal and coronary

Small arteries and arterioles

• Capillaries

• Veins; post-capillary venules, collecting venules, veins.

Vascular organization

• Large elastic arteries > medium-sized arteries > small arteries >arterioles > capillaries > post-capillary venules > collecting venules > veins

Lymphatics

• Endothelium-lined channels that drain excess interstitial tissue fluid, eventually returning it to blood via the thoracic ducts.

2.VASCULAR WALL CELLS AND THEIR RESPONSE TO INJURY

• Endothelial cells;Elaboration of Anticoagulant, Antithrombotic,

Fibrinolytic Regulators

Elaboration of Prothrombotic Molecules

Extracellular Matrix Production (Collagen, Proteoglycans)

Modulation of Blood Flow and Vascular Reactivity

Regulation of Inflammation and Immunity

Regulation of Cell Growth

Oxidation of LDL

Ctd

• Vascular Smooth Muscle Cells proliferate when appropriately stimulated

synthesize ECM collagen, elastin, and proteoglycans

elaborate growth factors and cytokines

vasoconstriction or vasodilation

Response of Vascular Wall Cells to Injury

• Endothelial injury contributes to a host of pathologies including thrombosis, atherosclerosis, and hypertensive vascular lesions.

• Injury to the vessel wall results in a healing response, involving intimal expansion by proliferating SMCs and newly synthesized ECM.

• The recruitment and activation of the SMCs in this process involves signals from cells eg ECs, and mediators derived from coagulation and complement cascades.

• Therefore, intimal thickening is a stereotyped Response to Vascular Injury

3.CONGENITAL ANOMALIES

• Rarely symptomatic;Developmental (berry) aneurysms occur in cerebral

vessels.

Arteriovenous fistulas are direct connections between arteries and veins that bypass the intervening capillaries.

Fibromuscular dysplasia is a focal irregular thickening of the walls of medium and large muscular arteries.

4.ARTERIOSCLEROSIS

• Arterial wall thickening and loss of elasticity.Arteriolosclerosis affects small arteries and arterioles with

two anatomic variants hyaline and hyperplastic.

Mönckeberg medial calcific sclerosis; calcific deposits in muscular arteries.

Atherosclerosis.

5.ATHEROSCLEROSIS

• General descriptions;intimal lesions called atheromas (also called

atheromatous or atherosclerotic plaques), that protrude into vascular lumina.

plaque consists of a raised lesion with a soft, yellow, grumous core of cholesterol (esters) covered by a firm, white fibrous cap.

obstructs blood flow & weaken the underlying media and rupture, causing acute catastrophic vessel thrombosis.

causes ischemic heart disease (IHD) .

Epidemiology

• Causes more morbidity and mortality (roughly half of all deaths) in the Western world than any other disorder.

• The mortality rate for IHD in the United States is among the highest in the world and is approximately five times higher than that in Japan.

• Japanese who immigrate to the United States and adopt American lifestyles and dietary customs acquire the same predisposition to atherosclerosis as the homegrown population.

Major Constitutional Risk Factors for IHD

• Nonmodifiable factors;Age; between ages 40 and 60, the incidence of myocardial

infarction in men increases fivefold.

Gender; premenopausal women are relatively protected against atherosclerosis and its consequences compared with age-matched men.

Genetics; well-established familial predisposition to atherosclerosis and IHD is multifactorial:such as hypertension or diabetes, familial hypercholesterolemia, that result in excessively high blood lipid levels.

• Major Modifiable Factors; Hyperlipidemia; esp. hypercholesteremia i.e. LDL cholesterol

has an essential physiologic role delivering cholesterol to peripheral tissues while mobilizes cholesterol from developing and existing atheromas.

Hypertension; increase the risk of IHD by approximately 60% in comparison with normotensive populations.

Cigarette Smoking; Prolonged (years) smoking of one pack of cigarettes or more daily increases the death rate from IHD by 200%.

Diabetes Mellitus; induces hypercholesterolemia, the incidence of myocardial infarction is twice as high in diabetic as in nondiabetic individuals.

• Additional Factors; Inflammation as marked by C-reactive protein.

Hyperhomocystinemia.

Lipoprotein a.

Factors Affecting Hemostasis.

Other Factors; like lack of exercise; competitive, stressful lifestyle ("type A" personality); and obesity.

Pathogenesis

• Response-to-injury hypothesis;Atherosclerosis as a chronic inflammatory response of the

arterial wall to endothelial injury.

Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the normal cellular constituents of the arterial wall.

• Central tenets of the hypothesis;Chronic endothelial injury, with resultant endothelial

dysfunction, causing (among other things) increased permeability, leukocyte adhesion, and thrombosis.

Accumulation of lipoproteins (mainly LDL and its oxidized forms) in the vessel wall.

Monocyte adhesion to the endothelium, followed by migration into the intima and transformation into macrophages and foam cells.

Platelet adhesionFactor release from activated platelets, macrophages, and vascular wall cells, inducing

SMC recruitment, either from the media or from circulating precursors.

SMC proliferation and ECM production. Lipid accumulation both extracellularly and within cells

(macrophages and SMCs).

Morphology

• Fatty Streaks; composed of lipid-filled foam cells but are not significantly raised, begin as multiple minute yellow, flat spots that can coalesce into elongated streaks,

• Atherosclerotic Plaque; a.k.a fibrous or fibrofatty plaques impinge on the lumen of the artery and grossly appear white to yellow; thrombosis superimposed over the surface of ulcerated plaques is red-brown in color.

• Atherosclerotic plaques have three principal components: (1) cells, including SMCs, macrophages, and T cells; (2) ECM, including collagen, elastic fibers, and proteoglycans; and (3) intracellular and extracellular lipid.

• Parts of the plaque(on cross-section): Superficial fibrous cap is composed of SMCs and relatively dense collagen. “Shoulder”- beneath and to the side of the cap = more cellular area containing macrophages,

T cells, and SMCs. Necrotic core; deep to the fibrous cap, containing cholesterol (esters), debris from dead cells,

foam cells (lipid-laden macrophages and SMCs), fibrin, variably organized thrombus, and other plasma proteins; the cholesterol content is frequently present as crystalline aggregates that are washed out during routine tissue processing and leave behind only empty "clefts.“

Neovascularization at the periphery of the lesions,

m

• Plaque changes;Rupture, ulceration, or erosion; exposes the bloodstream to

highly thrombogenic substances and induces thrombus formation and occlude the lumen and lead to downstream ischemia.

Hemorrhage into a plaque

Atheroembolism; plaque rupture can discharge debris into the bloodstream, producing microemboli composed of plaque contents.

Aneurysm formation; Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes weakness of the vessel wall and development of aneurysms that may rupture

Natural History of Atherosclerosis

• Preclinical and clinical phase.

Prevention of Atherosclerotic Vascular Disease

• Primary prevention programs; cessation of cigarette smoking, control of hypertension, weight loss, exercise, and lowering total and LDL blood cholesterol levels while increasing HDL (e.g., by diet or through statins)

• Secondary prevention programs; use of aspirin (anti-platelet agent), statins, and beta blockers (to limit cardiac demand), as well as surgical interventions (e.g., coronary artery bypass surgery, carotid endarterectomy). These can successfully reduce recurrent myocardial or cerebral events.

6.HYPERTENSIVE VASCULAR DISEASE

• General description; Elevated blood pressure is called hypertension.

Remains asymptomatic until late in its course.

Contributes to the pathogenesis of coronary heart disease and cerebrovascular accidents, causes cardiac hypertrophy and heart failure, aortic dissection, and renal failure.

Regulation of Blood Pressure

• BP= CO X PR

• RAA System

• Vasodilators

• Adrenal aldosterone

• ANP

Pathogenesis of Hypertension

• 90% to 95% of hypertension is idiopathic (essential hypertension), which is compatible with long life, unless a myocardial infarction, cerebrovascular accident, or other complication supervenes.

• Most of the remainder of "benign hypertension" is secondary to renal disease or, less often, to narrowing of the renal artery, usually by an atheromatous plaque (renovascular hypertension).

• Accelerated or malignant hypertension, the clinical syndrome is characterized by severe hypertension (diastolic pressure over 120mmHg), renal failure, and retinal hemorrhages and exudates, with or without papilledema

• Essential Hypertension; alterations in renal sodium homeostasis and/or vessel wall tone or

structure underlie essential hypertension.

interplay of multiple genetic and environmental factors affecting cardiac output and/or peripheral resistance.

• Secondary Hypertension; Renal: acute glomerulonephritis, chronic renal disease, polycystic

disease, renal artery stenosis, renal vasculitis, renin-producing tumors.

Endocrine: Adrenocortical hyperfunction, Exogenous hormones, Pheochromocytoma, Acromegaly, Hypo/hyperthyroidism, Pregnancy-induced.

Cardiovascular: Coarctation of aorta , polyarteritis nodosa increased intravascular volume , increased cardiac output , rigidity of the aorta.

Neurologic: psychogenic , increased intracranial pressure , sleep apnea, acute stress (surgery).

Vascular Pathology in Hypertension

• Accelerating atherogenesis• Potentiate both aortic dissection and

cerebrovascular hemorrhage• Two forms of small blood vessel disease

Hyaline Arteriolosclerosis: a homogeneous pink hyaline thickening of the walls of arterioles with loss of underlying structural detail and with narrowing of the lumen

Hyperplastic Arteriolosclerosis. Related to acute or severe elevations of blood pressure, characteristic of malignant hypertension , associated with "onion-skin," concentric, laminated thickening of the walls of arterioles with luminal narrowing ,the laminations consist of SMCs and thickened, duplicated basement membrane.

7.ANEURYSMS AND DISSECTIONS

• General description;aneurysm is a localized abnormal dilation of a blood vessel

or the heart "true" aneurysm. false aneurysm (pseudoaneurysm): pulsating hematoma.

arterial dissection arises when blood enters the wall of the artery, as a hematoma dissecting between its layers.

Causes; atherosclerosis and cystic medial degeneration of the arterial media, wall-weakening factors like include trauma, congenital defects (e.g., berry aneurysms), infections (mycotic aneurysms), or syphilis, and vasculitis.

Mycotic aneurysms can originate (1) from embolization of a septic thrombus, usually as a complication of infective endocarditis; (2) as an extension of an adjacent suppurativeprocess; or (3) by circulating organisms directly infecting the arterial wall.

Abdominal Aortic Aneurysm

• Definition

Out pouching of the aorta, most commonly in abdominal aorta, following

atherosclerotic destruction of the aortic media, leading to vessel wall weakness

• Morphology Big fusiform or sacular bulge out the side of the

abdominal aorta of varying width and length below the renal arteries and above the bifurcation of the aorta.

Often contains atheromatous ulcers with thrombi (source of atherothrombotic origin)

May be so large that it compresses nearby vessels or the thrombus causes occlusion syndromes

Special Variants• Inflammatory AAA = Macrophages, Giant Cells, Lymphocytes,

Plasma cells, AAA• Mycotic AAA = Supuritic lesions with organisms hiding inside

(salmonella)

S

• Pathogenesis Atherosclerosis is number 1 cause

Cystic Medial Degeneration = Collagen. Aneurysms come from abnormal collagen

(Marfan’s) or an abnormality of collagen remodeling (increased degradation decreased

synthesis caused by an immune reaction) resulting in an inherently weakened aortic wall

• Clinical Course Rupture is often fatal. Hemorrhage occurs into the

peritoneum. ↑size = ↑risk

Obstruction of a vessel (mesenteric, renal, vertebral) leading to ischemic injury

Direct Compression of the ureter or of the vertebrae (casing vertebral erosion)

Embolism from the thrombus that’s sitting inside

Tumor = AAA is a palpable mass that may

Syphilitic Aneurysm

• Causeobliterative endarteritis characteristic of the tertiary

stage of syphilis can involve small vessels in any part of the body.

Syphilis (stage 3) has a vascular predilection for small vessels, especially of the aorta

Infection with subsequent Inflammation of the vasavasorum leads to obstruction, inducing ischemia and obliterative endarteritis of the aorta, causing death of muscle and elastic tissue, called syphilitic aortitis

• MorphologyStarts in the adventitia with vessels with

inflammation reactions in adventitia.syphilitic aortitis.Muscle that dies is replaced with fibrous scar

tissue in the media, contraction of which causes the “tree‐barking” appearance

Effects thoracic aorta with possible dilation of aortic valve leading to insufficiency

• PresentationAll causes by the encroachment on

mediastinal tissues• Crush the lungs = Dyspnea Pain from

rib and vertebral erosions Death from rupture

• Crush the esophagus = Dysphagia, Cardiac Disease from valve involvement Aortic Regurgitation

Aortic Dissection

• Definitionblood splays apart the laminar planes of the media to

form a blood-filled channel within the aortic wall

ruptures through the adventitia and into various spaces, where it causes either massive hemorrhage or cardiac tamponade (hemorrhage into the pericardial sac).

men aged 40 to 60 years, with antecedent hypertension (> 90% of cases ), and younger patients with systemic or localized abnormalities of connective tissue affecting the aorta ( Marfan’s )

• MorphologyA single intimal tear cuts into but not through the

media of the ascending aorta creating a blood filled pocket within the aorta, between layers

Dissection can continue in both direction (towards the heart and towards the femoral)

Usually rupture outwards, but can rupture back inwards

– Outward = hemorrhage = fatal

– Inward = second intimal tear back into the normal lumen, forming a new vascular channel (“double‐barrel Aorta”) which can, over time, endothelize and become a permanent vessel.

No distinguishing histology except for warning signs = elastic tissue fragmentation and medial degeneration

• PathogenesisHTN is primary causative agent, if you see HTN pick

Dissecting Hematoma

Medial weakening is not required for dissection, but cystic medial necrosis from

Marfan’s or Ehler’s Danlos (weak elastic layer) predisposes dissection

If you have a dissection, pick HTN. If HTN isn’t there, pick Marfans

Once dissection has happened, arterial blood pressure favors hematoma

• Clinical CourseIf the dissection is Proximal subclavian/carotid (type A

= bad), if distal (type B = better)

Pain in the chest radiating to the back is a tell tale sign

Death usually results from rupture

If dissection involves aortic root, you can get valve problems (regurgitation, murmur

Classification of dissections

8.VASCULITIS

• General description;Inflammation of vessel walls.

2 mechanisms: immune-mediated inflammation and direct invasion of vascular walls by infectious pathogens.

Noninfectious Vasculitis.

Infectious Vasculitis.

Vasculitis Associated with Other Disorders .

Non-infectious Vasculitis.

• Classification;Large-Vessel Vasculitis

» Giant-cell (temporal) arteritis

» Takayasu arteritis

Medium-Vessel Vasculitis» Polyarteritis nodosa

» Kawasaki disease

Small-Vessel Vasculitis» Wegener granulomatosis

» Churg-Strauss syndrome

» Microscopic polyangiitis

• Pathogenesis; immune complex deposition; Antibody and complement are

typically detected in vasculitic lesions, DNA-anti-DNA complexes(SLE) and drug hypersensitivity.Can be 2ndary to viral infections.

antineutrophil cytoplasmic antibodies (ANCAs); circulating antibodies that react with neutrophil cytoplasmic antigens. Cytoplasmic localization (c-ANCA) >>proteinase-3 (PR3) and Perinuclear localization (p-ANCA) >>myeloperoxidase (MPO).

anti-endothelial cell antibodies; Antibodies to ECs may predispose to certain vasculitides, for example Kawasaki disease.

• Giant-Cell (Temporal) ArteritisMost common form of Vasculitis, especially in Elderly Women affects the arteries in the head-esp. the temporal arteries-but

also the vertebral and ophthalmic arteries & the aorta (giant-cell aortitis).

T cell-mediated immune response to an unknown vessel wall antigen.

nodular intimal thickening with reduction of the lumen and occasional thrombosis.

granulomatous inflammation within the inner media centered on the internal elastic membrane.

fragmentation of the internal elastic laminaHead pain, vision disturbances /blindness(ophthalmic artery

involved)Responds well to steroids.

• Takayasu Arteritis"pulseless disease“transmural fibrous thickening of the aorta-

particularly the aortic arch and great vessels.severe luminal narrowing of the major branch

vessels- loss of pulse.in women younger than 40 years of

age(Japanese population)intimal hyperplasia and irregular thickening of

the vessel wall

adventitial mononuclear infiltrates >> mononuclear inflammation in the media >> granulomatous inflammation(giant cells and patchy medial necrosis)

reduced blood pressure and weaker pulses in the upper extremities with coldness or numbness of the fingers; ocular disturbances, and neurologic deficits. Claudication of the legs(distal aorta involved); pulmonary hypertension(PA involved). Narrowing of the coronary ostia >>MI, systemichypertension(renal arteries involved)

• Polyarteritis NodosaInvolves renal and visceral vessels but not the pulmonary

circulation. segmental transmural necrotizing inflammation of small to

medium-sized arteriespart of the vessel circumference involved, with a

predilection for branch points.weakens the arterial wall >>aneurysms or even rupture.Impaired perfusion >>in the distribution of affected vessels transmural inflammation >>fibrinoid necrosis >>fibrous

/nodular thickening of the vessel wall that can extend into the adventitia(which may coexist)

• Kawasaki Disease self-limited illness of infancy and childhood (80% of patients

are younger than 4 years) coronary arteritis >>aneurysms that rupture or thrombose,

causing AMI.leading cause of acquired heart disease in children.delayed-type hypersensitivity -T cells to uncharacterized

vascular antigen.pronounced inflammation affecting the entire thickness of the

vessel wall.Clinical Course: mucocutaneous lymph node syndrome with

conjunctival & oral erythema and erosion, edema of the handsand feet, erythema of the palms and soles, a desquamativerash, and cervical lymph node enlargement

• Microscopic Polyangiitis• necrotizing vasculitis that affects capillaries , arterioles and

venules. • hypersensitivity vasculitis or leukocytoclastic vasculitis.• necrotizing glomerulonephritis (90% of patients) and pulmonary

capillaritis present.• an antibody response to antigens such as drugs (e.g., penicillin),

microorganisms (e.g., streptococci), heterologous proteins, or tumor proteins.

• segmental fibrinoid necrosis of the media- with focal transmuralnecrotizing lesions

• granulomatous inflammation is absent.• infiltrating and fragmenting neutrophils- in postcapillary venules.• little or no immunoglobulin can be seen in most lesions (so-called

"pauci-immune" injury).

• Wegener GranulomatosisTriad

– Acute necrotizing granulomas of the upper respiratory tract – Necrotizing or granulomatous vasculitis– Renal disease in the form of focal necrotizing, often crescentic,

glomerulonephritis.

cell-mediated hypersensitivity response, possibly to an inhaled infectious or other environmental agent.

The upper respiratory tract lesions range from inflammatory sinusitis with mucosal granulomas to ulcerative lesions of the nose, palate, or pharynx, rimmed by granulomas with geographic patterns of central necrosisand accompanying vasculitis

renal lesions

Clinical Features • persistent pneumonitis with bilateral nodular and cavitary

infiltrates

• chronic sinusitis (90%),

• mucosal ulcerations of the nasopharynx (75%), and evidence of renal disease (80%).

• Other features include rashes, muscle pains, articularinvolvement, mononeuritis or polyneuritis, and fever

• Allergic granulomatosis and angiitis (Churg-Strauss syndrome) has association with allergic rhinitis, bronchial asthma, and peripheral eosinophilia; p-ANCAs are present in roughly half the patients.

• Thromboangiitis ObliteransBuerger Disease

segmental, thrombosing acute and chronic inflammation(tibial and radial arteries)

exclusively in heavy smokers of cigarettes, usually beginning before age 35.

direct toxicity to endothelium by some tobacco products, or an idiosyncratic immune response to the same agents

sharply segmental acute and chronic vasculitis of medium-sized and small arteries, predominantly of the extremities.

superficial nodular phlebitis, cold sensitivity of the Raynaudtype in the hands, and instep claudication.

Vasculitis Associated with Other Disorders

• Disorders; rheumatoid arthritis, SLE, malignancy, or systemic illnesses such as mixed cryoglobulinemia, antiphospholipidantibody syndrome and Henoch-Schönleinpurpura

• Rheumatoid vasculitis

• Lupus vasculitis

Infectious Vasculitis

• Direct invasion of infectious agents;Aspergillus and Mucor species

mycotic aneurysms

can induce thrombosis and infarction.

9.RAYNAUD PHENOMENON

• Results from an exaggerated vasoconstriction of digital arteries and arterioles

• Two types;Primary Raynaud phenomenon; exaggeration of

central and local vasomotor responses to cold or emotion(common in young women)

Secondary Raynaud phenomenon; vascular insufficiency of the extremities due to arterial disease from other entities (SLE, scleroderma, Buerger disease or atherosclerosis).

10.VEINS AND LYMPHATICS

• Varicose VeinsSuperficial veins (usually of the legs) become

distended, more cosmetic than anything else

Obesity, jobs with legs dependent (barber, surgeon), and pregnancy are disposing factors

Stasis of blood, rupture of valves, or thinning of walls allows distention

May cause ulceration, but are generally asymptomatic (do not cause emboli)

Can also be in the esophagus (esopheal varices) and in the anus (hemorrhoids).

• Thrombophlebitis and PhlebothrombosisAka Deep Vein Thrombosis, DVT.

The distinction between thrombosis of the vein (phlebothrombosis) and inflammation of the

Vein with thrombosis (thrombophlebitis) is not relevant, they are all DVTs

Presents with pain in the calf with red, tender lesions, with a positive Homan’s Sign(dorsiflexion induces pain)

Risk increases with Estrogen, Birth Control, Smoking, Age, Hypercoagulability

Can result in pulmonary embolism or edema

• Superior and Inferior Vena Caval Syndromes Something blocks these large veins (invasive neoplasm,

mural thrombosis) that causes a back up distally, without a failure of the heart

Massive edema inferiorly for IVC (ankle, ascites, pelvis) or superiorly for SVC (face, neck, arms)

• Lymphangitis and LymphedemaInfection gets into the lymph nodes.

Red streaks from site of penetration, follows along lymph tract, finished at lymph node.

Lymphadenopathy is present with PMNs and Lymphocytes infiltrating site of infection.

Caused by Cancer or Virulent Bacteria (Staph).

11.TUMORS

• Classification of Vascular Tumors and Tumor-like Conditions Benign Neoplasms, Developmental and Acquired Conditions

– Hemangioma– Capillary hemangioma– Cavernous hemangioma– Pyogenic granuloma Lymphangioma– Simple (capillary) lymphangioma– Cavernous lymphangioma (cystic hygroma) – Glomus tumor – Vascular ectasias– Nevus flammeus– Spider telangiectasia (arterial spider) – Hereditary hemorrhagic telangiectasis (Osler-Weber-Rendu disease)– Reactive vascular proliferations – Bacillary angiomatosis

Intermediate-Grade Neoplasms– Kaposi sarcoma – Hemangioendotheliom

Malignant Neoplasms– Angiosarcoma– Hemangiopericytoma

• Benign Tumors and Tumor-like Conditions Hemangioma

– Capillary Hemangioma

– Cavernous Hemangioma

– Pyogenic Granuloma

Lymphangioma– Simple (Capillary) Lymphangioma

– Cavernous Lymphangioma (Cystic Hygroma)

Glomus Tumor (Glomangioma)

Vascular Ectasias– Nevus Flammeus

– Spider Telangiectasia

– Hereditary Hemorrhagic Telangiectasia (Osler-Weber-Rendu Disease)

Bacillary Angiomatosis

• Intermediate-Grade (Borderline Low-Grade Malignant) Tumors

Kaposi Sarcoma – Chronic KS

– Lymphadenopathic KS (also called African or endemic KS)

– Transplant-associated KS

– AIDS-associated (epidemic) KS

Hemangioendothelioma– Epithelioid hemangioendothelioma

• Malignant Tumors Angiosarcoma

Hepatic angiosarcomas

Lymphangiosarcoma

Hemangiopericytoma

12.PATHOLOGY OF VASCULAR INTERVENTION

• Endovascular Stenting

• Vascular Replacement