Blood Vessels and Their Structure

🔄 General Function of Blood Vessels

Blood vessels form a closed circuit for blood to circulate throughout the body.
Oxygen-rich blood is pumped from the left side of the heart, travels to all body cells, and returns oxygen-poor blood to the right side of the heart.

🛤️ Types of Blood Vessels

Blood travels through the following vessels in order:

Arteries – carry blood away from the heart.
Arterioles – smaller branches of arteries.
Capillaries – the smallest vessels where exchange of gases and nutrients occurs.
Venules – small veins collecting blood from capillaries.
Veins – carry blood back to the heart.

🧠 Arteries: Structure & Types

Arteries are classified based on size and wall structure into:

Type	Key Features
Large (Elastic)	Rich in elastic tissue. Example: Aorta.
Medium (Muscular)	Rich in smooth muscle. Example: Coronary arteries.
Arterioles	Smallest arteries, control blood flow into capillaries.

🧱 Arterial Wall Structure (All arteries have 3 layers)

1. Tunica Intima (Inner layer)

Endothelium: A thin layer of flat cells lining the inside of the artery. Helps regulate blood flow and prevents clots.
Subendothelial tissue: Loose connective tissue, contains collagen, elastin, and other structural proteins.
Internal Elastic Lamina: A thin elastic sheet that allows the artery to stretch.

2. Tunica Media (Middle layer)

Thickest layer.
Contains smooth muscle cells and elastic fibers.
Helps control blood pressure and flow by contracting or relaxing.
Has an External Elastic Lamina, a less-defined elastic layer.

3. Tunica Adventitia (Outer layer)

Made of connective tissue and elastic fibers.
Contains nerve fibers and lymphatic vessels.
Nourishes the artery wall.

🧪 Nutrient Supply to Arterial Wall

Inner layers get nutrients by diffusion from the blood inside the artery.
Outer layers are supplied by small blood vessels called vasa vasorum ("vessels of the vessels").

🔬 Structural Changes with Size

As arteries become smaller (from large arteries to arterioles), the thickness of all 3 layers decreases.
Elastic tissue reduces, and eventually elastic lamina disappears in arterioles.

🧵 Arterioles

Very small arteries (20-100 µm).
Have thin walls:
- 1 layer of endothelium.
- 1-2 layers of smooth muscle.
- Minimal connective tissue.
No visible elastic lamina.

Capillaries

Diameter: 7-8 µm (same as a red blood cell).
Only one thin endothelial layer.
Main site for exchange of gases, nutrients, and waste.

Blood Flow Pathway

Heart ➝ Arteries ➝ Arterioles ➝ Capillaries ➝ Venules ➝ Veins ➝ Heart

🔍 Arteriosclerosis

Arteriosclerosis is a general term used to describe the thickening and hardening of artery walls, leading to reduced elasticity and narrowed blood flow.

💡 Key Term:

Arteriosclerosis = Hardening of arteries.

🧠 Types of Arteriosclerosis:

There are four main types:

1️⃣ Senile Arteriosclerosis

Occurs due to aging, affecting many arteries.

🔬 Morphologic Features:

Fibroelastosis: Thickening of inner and middle layers due to increased collagen and elastic tissue.
Elastic Reduplication: The internal elastic lamina splits, forming two wavy layers.

🩺 Result: Can lead to increased systolic blood pressure in elderly people.

2️⃣ Hypertensive Arteriolosclerosis

Seen in people with high blood pressure (hypertension).
Affects small arteries and arterioles.

💡 3 Types:

i. Hyaline Arteriolosclerosis

Walls of arterioles become thick and glassy (hyaline).
Lumen becomes narrow or blocked.

🧪 Pathogenesis (Possible Causes):

Leakage of plasma proteins due to vessel wall stress.
Damage from high blood pressure or diabetes.
May also be part of normal aging.

ii. Hyperplastic Arteriolosclerosis

Common in malignant (very high) hypertension.

🔬 Morphologic Features:

Onion-skin appearance: Multiple layers of smooth muscle cells in the intima.
Other types:
- Mucinous thickening: Deposits of jelly-like substances.
- Fibrous thickening: Collagen and hyaline material buildup.

🧪 Pathogenesis:
Due to endothelial damage caused by high pressure → repair response → thickening.

iii. Necrotising Arteriolitis

Seen in severe or malignant hypertension.

🔬 Features:

Fibrinoid necrosis: Vessel wall cells die and form debris.
Neutrophils: Immune cells infiltrate the area.
Surrounding bleeding and swelling.

🧪 Cause:
Sudden spike in blood pressure causing direct injury to vessel walls.

3️⃣ Mönckeberg’s Arteriosclerosis

Also called Medial Calcific Sclerosis.
Affects medium and large muscular arteries, especially in the legs and genital area, usually in people above 50.

💡 Key Points:

Calcium is deposited in the media (middle layer).
No inflammation.
Lumen remains open – blood flow is not affected.
Found incidentally on X-rays.

🧪 Cause:
Considered an age-related degenerative change (possibly due to repeated vasoconstriction).

📌 Summary Table:

Type	Cause	Affected Area	Main Feature
Senile	Aging	Media & Intima	Thickening, elastic changes
Hyaline	HTN, Diabetes, Aging	Arterioles	Hyaline material deposits
Hyperplastic	Malignant HTN	Intima	Onion-skin smooth muscle
Necrotising	Sudden HTN	Arterioles	Fibrinoid necrosis
Mönckeberg's	Aging	Media	Calcium deposits, no narrowing

🧠 Important Terms Explained:

HTN = Hypertension = High Blood Pressure
Lumen = The hollow space inside a blood vessel
Intima/Media/Adventitia = The three layers of the artery wall
Fibrinoid Necrosis = Cell death + fibrin-like material in walls
Onion-skin lesion = Layered thickening of vessel walls
Hyaline = A glassy, pink-staining material seen in tissues
Calcification = Deposit of calcium salts in tissue

4. Atherosclerosis

🧬 Definition

Atherosclerosis is a type of arteriosclerosis where fatty plaques (atheromas) develop in the intima (inner lining) of large and medium-sized arteries.

Word origin:

Athero- = "gruel" or "porridge" (soft, lipid core)
-Sclerosis = "hardening" (fibrous cap and connective tissue)

🫀 Commonly affected arteries:

Aorta
Coronary arteries
Cerebral arteries
Peripheral arteries

🚨 Clinical Consequences of Atherosclerosis

Heart:

Angina (chest pain)
Myocardial infarction (heart attack)
Chronic ischemic heart disease

Brain:

Transient ischemic attacks (TIAs)
Cerebral infarcts (strokes)
Ischemic encephalopathy

Other:

Peripheral arterial disease
Mesenteric ischemia
Aneurysm formation

🧾 Etiology (Causes & Risk Factors)

Major Risk Factors

🛠️ Modifiable:

Dyslipidemia (abnormal cholesterol/triglycerides)
Hypertension (high BP)
Smoking
Diabetes Mellitus

📌 Non-Modifiable:

Age
Male gender
Genetic predisposition
Family history

🌱 Emerging Risk Factors

Obesity
Lack of exercise
Inflammation (high CRP)
Stress
Hormonal imbalances (e.g. postmenopausal estrogen loss)
Infections (e.g. Chlamydia pneumoniae)

💊 Modifiable Risk Factors in Detail

1. Dyslipidemia

Lipoproteins:

LDL = “Bad” cholesterol → deposits fat in arteries
HDL = “Good” cholesterol → removes fat from arteries

📉 Normal levels:

Lipid	Normal Range	Risk Impact
Total Cholesterol	< 200 mg/dL	↑ = High risk
LDL	< 130 mg/dL	↑ = Very atherogenic
HDL	> 60 mg/dL	↑ = Protective
Triglycerides	< 160 mg/dL	↑ = Risk factor

🧬 Familial hypercholesterolaemia:

Genetic condition
↑ LDL
Normal triglycerides
Early atherosclerosis and heart attacks

Management:

Diet & exercise
Statins
HDL boost with niacin

2. Hypertension

Blood pressure >160/95 mmHg:

Causes mechanical stress on artery walls
↑ Risk by 5x

🎯 Goal BP: <140/90 mmHg

3. Smoking

Decreases HDL, increases clotting
Forms carboxyhemoglobin → ↓ oxygen to arterial walls
Causes hypoxia and injury
3–5x ↑ risk of heart disease

4. Diabetes Mellitus

Type 2 diabetes strongly linked to atherosclerosis
Common complications:
- Double risk of heart attack
- Higher stroke risk
- 🦶 100x ↑ risk of gangrene

📜 Constitutional (Non-Modifiable) Risk Factors

Age

Lesions start early (even in childhood), worsen with age

Gender

Males > Females (before menopause)
Estrogen is protective

Genetics & Race

Family history increases risk
Some racial groups more prone (e.g. South Asians)

🌱 Emerging Risk Factors in Atherosclerosis

These are nontraditional and newly recognized factors whose role in causing atherosclerosis is not yet fully established, but evidence is growing.

1. Environmental Influence

Higher incidence in developed countries suggests environmental and lifestyle factors (e.g., diet, pollution, urban stress) contribute to disease.

2. Obesity

If body weight is 20% or more above ideal, the risk of atherosclerosis significantly increases.
📈 Obesity is linked with:

↑ LDL
↓ HDL
Insulin resistance
Inflammation

3. Hormonal Factors

Exogenous hormones (e.g., oral contraceptives)
Endogenous estrogen deficiency in post-menopausal women

🔺 Associated with increased risk of heart attacks and strokes

4. Physical Inactivity

Sedentary lifestyle & lack of exercise increases the chance of:

Obesity
Dyslipidaemia
Insulin resistance
Endothelial dysfunction

Regular activity improves vascular health and lipid profile

5. Stress & Personality Type

People with “Type A” personality (aggressive, competitive, time-urgent) are at greater risk of Ischemic Heart Disease (IHD) compared to “Type B” (relaxed, easygoing).

🧠 Stress hormones (like cortisol, adrenaline) may damage blood vessels over time.

6. Homocystinuria

A rare inborn error of metabolism
⚠️ Patients have high homocysteine levels → linked to early atherosclerosis and coronary artery disease

7. Prothrombotic State

Elevated fibrinogen levels
Other clot-promoting substances

🧨 These factors can trigger thrombus formation, the most dangerous complication of atherosclerosis.

8. Infections

Pathogens found in atherosclerotic plaques:

Chlamydia pneumoniae
Herpesvirus
Cytomegalovirus (CMV)

They may promote inflammation and plaque instability, often in synergy with other risk factors.

9. Markers of Inflammation

C-Reactive Protein (CRP) – an acute phase reactant
📊 High CRP levels = higher risk of developing or worsening atherosclerosis

🧠 Inflammation plays a central role in atheroma formation and rupture.

🩺 Pathogenesis

Accepted steps in the development of atherosclerosis.

🩹 1. Endothelial Injury – The First Trigger

Endothelial dysfunction, not necessarily full denudation (loss or stripping away of a surface layer), initiates plaque formation.
Causes in animals:
- Mechanical trauma
- Hemodynamic forces
- Chemical/toxic agents
- Metabolic conditions (e.g., dyslipidemia, homocysteine)
- Infections, toxins, tobacco, radiation
💡 Plaques commonly form at arterial branches due to high shear stress

🧬 2. Intimal Smooth Muscle Cell Proliferation

Endothelial injury → platelet adhesion + inflammation → smooth muscle cell proliferation
Stimulated by cytokines: IL-1, TNF-α (from invading monocyte-macrophages and
by activated platelets)
Key growth factors:
- PDGF, FGF → migration & proliferation of smooth muscle cells into intima
- TGF-β, IFN-γ → regulate collagen synthesis
Molecules involved: Nitric oxide, Endothelin (from endothelium)
Smooth muscle cells produce matrix proteins: Collagen, Elastic fibers, and Proteoglycans

🧲 3. Role of Blood Monocytes

Plasma LDL enters intima and undergoes oxidation → becomes oxidized LDL
Oxidized LDL functions:
- Attracts & activates monocytes
- Taken up by scavenger receptors on monocytes → transforms into foam cells
Oxidized LDL is toxic to endothelium
Foam cells undergo apoptosis, releasing lipids → form lipid core of plaque

🧪 4. Role of Dyslipidaemia

Chronic dyslipidemia promotes endothelial dysfunction and increases permeability
LDL (bad cholesterol) → forms foam cells
HDL (good cholesterol) → anti-atherogenic (protective)

🩸 5. Thrombosis – Final Plaque Evolution

Endothelial damage exposes subendothelial connective tissue → triggers:
- Platelet aggregation
- Smooth muscle proliferation
Small platelet clots + inflammation + foam cells = atheromatous plaque
Fibrin and circulating cells may attach to lesion → thrombus becomes part of plaque

Morphologic Features of Atherosclerosis

🟡 1. Fatty Streaks & Dots

Seen in infancy, regress with age.
Location: Posterior aorta
Microscopy: Foam cells, lipid-rich SMCs, ECM, few lymphocytes.

🌫 2. Gelatinous Lesions

Grey, raised, round/oval lesions (~1cm).
Histology: Increased ground substance + thinned endothelium.

⚪️ 3. Atheromatous Plaques (Fibrous/Fibrofatty Plaques, Atheromas)

Common in elderly, advanced lesions.
Locations:
- Abdominal aorta
- Coronaries, carotids, cerebrals, femoral, iliac arteries.
Gross: White/yellow, raised plaques with firm fibrous cap and soft yellow core.
Microscopy:
- Fibrous cap: SMCs, collagen, proteoglycans, endothelium.
- Cellular layer: Macrophages, lymphocytes, foam cells.
- Core: Necrosis, cholesterol clefts, fibrin, lipid debris.

⚠️ 4. Complicated Plaques

i) Calcification

Eggshell-like cracking in aorta/coronaries.
Histology: Calcium near necrotic/lipid zones.

ii) Ulceration

Rupture of fibrous cap → Lipid emboli → Yellow ulcer base.
Can lead to sudden coronary occlusion.

iii) Thrombosis

Over ulcerated plaques → Mural thrombi or occlusion.
May become emboli or undergo recanalization.

iv) Hemorrhage

Source: Ulceration or vasa vasorum rupture.
Common in coronaries.
Macrophages with hemosiderin present.

v) Aneurysm Formation

Media atrophy, fragmented elastic lamina.
Adventitial fibrosis → Wall weakening → Dilatation.

🏥 3. Clinical Effects of Atherosclerosis

General Effects

Chronic ischemia → Atrophy
Acute occlusion → Infarction
Thromboembolism
Aneurysm + rupture

Organ-Specific Outcomes

Aorta: Aneurysms, thrombi, emboli
Heart: MI, ischemic heart disease
Brain: Infarcts, chronic ischemia
Intestines: Ischemic bowel, infarction
Lower limbs: Intermittent claudication, gangrene

ARTERITIS (Angiitis / Vasculitis)

Definition:

Arteritis refers to inflammation of arteries or arterioles. It is also known as angiitis or vasculitis and may result from infectious or non-infectious causes. The non-infectious causes are more common clinically.

CLASSIFICATION OF ARTERITIS:

Type	Description
I. Infectious Arteritis	Caused by direct microbial invasion (bacteria, fungi) or hematogenous spread of infection.
II. Non-infectious Arteritis	Caused by immune-mediated, chemical, mechanical, or radiation-induced injury.

I. INFECTIOUS ARTERITIS

1. Endarteritis Obliterans

Definition: A non-specific response of arteries to chronic irritation (not a true inflammatory disease).
Associated with: Peptic ulcers, TB, chronic abscesses, meningitis, postpartum/postmenopausal uterus.
Gross: Lumen may appear normal externally but show luminal obliteration (a condition where the interior space of a tubular structure, such as a blood vessel or organ duct, is completely blocked or closed off) on section.
Microscopy:
- Intimal fibrosis with concentric, symmetrical fibrous tissue proliferation.
- Minimal or no inflammation, despite the “-itis” suffix.

2. Non-Syphilitic Infective Arteritis

Causes: Bacterial, fungal, parasitic, or viral infections via direct or hematogenous routes.
Microscopy:
- Inflammatory infiltrate in vessel walls.
- Lumen occlusion by thrombi → ischemic necrosis of supplied tissue.

3. Syphilitic Arteritis

Occurs in all stages of syphilis, especially the tertiary stage.
Two forms:
- Endarteritis (arterial wall)
- Periarteritis (periarterial tissue)
Common sites: Aorta and cerebral arteries

A. Syphilitic Aortitis

Location: Most commonly affects ascending aorta and aortic arch.
Gross Features:
- Aorta appears dilated and thickened.
- "Tree-bark" appearance: Intimal surface with pearly-white plaques separated by wrinkled areas.
Microscopy:
- Endarteritis and periarteritis of vasa vasorum in the media and adventitia.
- Perivascular plasma cells, lymphocytes, macrophages ± miliary gummas.
- Intimal fibrosis, collagenous, often hyalinized or calcified.
Consequences:
- Aortic aneurysm.
- Aortic valvular incompetence (rare today).
- Coronary ostial stenosis → myocardial fibrosis, angina, sudden death.

B. Cerebral Syphilitic Arteritis (Heubner’s Arteritis)

Involves small and medium cerebral arteries in tertiary syphilis.
Often coexists with syphilitic meningitis.
Gross: Thickened, rigid, white cerebral vessels.
Microscopy:
- Endarteritis and periarteritis.
- Medial muscle atrophy replaced by fibrosis → brain ischemia and atrophy.

non-infectious vasculitides

Polyarteritis Nodosa (PAN)

Type: Necrotizing vasculitis of small and medium-sized muscular arteries.
Etiology: Immune complex-mediated; triggered by infections (HBV, bacteria), drugs, etc.
Organs Affected: Kidneys, heart, GI tract, muscles, liver, nerves, testes, skin.
Clinical Features:
- Fever, malaise, weight loss
- Renal involvement: proteinuria, hematuria, renal failure
- GI symptoms: abdominal pain, melena
- Peripheral neuritis, hypertension
Gross: Beaded nodules at vessel bifurcations
Microscopy:
- Acute: Fibrinoid necrosis, neutrophils/eosinophils, thrombi, aneurysms
- Healing: Fibroblast proliferation, lymphocytes, plasma cells
- Healed: Dense fibrosis, loss of internal elastic lamina

Hypersensitivity Vasculitis (Microscopic Polyangiitis)

Also Known As: Allergic vasculitis, leukocytoclastic vasculitis
Vessels Affected: Venules, capillaries, arterioles (small vessels)
Causes: Infections, drugs, autoimmune diseases (RA, SLE), malignancies
Organs Affected: Skin, mucosa, lungs, brain, heart, kidneys
Microscopy:
- Leukocytoclastic: Fibrinoid necrosis, neutrophilic debris
- Lymphocytic: Lymphocyte-dominant; delayed-type hypersensitivity

Wegener’s Granulomatosis (Granulomatosis with Polyangiitis)

Triad:
1. Necrotizing granulomas (upper & lower respiratory tract)
2. Necrotizing vasculitis (lungs, airways)
3. Glomerulonephritis (focal or diffuse)
Organs Affected: Lungs, kidneys, sinuses, joints, skin, eyes, heart, CNS
Etiology: c-ANCA (anti-PR3)
Histology:
- Granulomas: necrosis, neutrophils, epithelioid & giant cells
- Vasculitis: segmental or circumferential
- Kidney: necrotizing glomerulonephritis

Temporal (Giant Cell) Arteritis

Type: Granulomatous arteritis of large and medium arteries
Common Sites: Temporal artery, aorta, carotids, subclavian
Demographic: Elderly (>70), females > males
Symptoms: Headache, visual loss, jaw claudication, polymyalgia rheumatica
Histology:
- Granulomatous inflammation around internal elastic lamina
- Giant cells, fragmentation of lamina
- Intimal thickening and luminal narrowing/thrombosis

Takayasu’s Arteritis (Pulseless Disease)

Type: Granulomatous vasculitis of large arteries (mainly aorta and branches)
Demographic: Young women
Symptoms: Absent upper limb pulses, ocular issues, ischemia-related symptoms
Gross: Thickened aortic wall, obliterated lumina
Histology:
- Panarteritis with mononuclear cells
- Perivascular inflammation of vasa vasorum
- Granulomas with necrosis, giant cells
- Advanced fibrosis

Kawasaki Disease (Mucocutaneous Lymph Node Syndrome)

Demographic: Infants and young children
Features:
- Fever, conjunctivitis, oral erosions, skin rash, cervical lymphadenopathy
Complications: Coronary artery aneurysms (major cause of pediatric heart disease)
Etiology: Unknown (possible infection, autoimmune, genetic)
Vessels: Coronary, renal, hepatic, mesenteric, pancreatic arteries

Key Immunologic Markers in Vasculitis

c-ANCA (anti-PR3): Wegener’s granulomatosis
p-ANCA (anti-MPO): Microscopic polyangiitis, glomerulonephritis
AECAs: Kawasaki disease, SLE, Buerger’s disease
Pauci-immune: Few/no immune deposits despite vasculitis (e.g., ANCA-associated types)

ANEURYSMS

📘 Definition

Permanent abnormal dilatation of a blood vessel due to congenital or acquired weakening/destruction of vessel wall. Common in large elastic arteries like the aorta. Can lead to thrombosis, rupture, embolism or compression of nearby structures

🗂️ Classification

A. Based on Wall Composition

True Aneurysm – All layers of the vessel wall involved
False Aneurysm – Wall composed of fibrous tissue (often post-trauma)

B. Based on Shape

Saccular – Large, spherical outpouching
Fusiform – Spindle-shaped dilatation
Cylindrical – Continuous, parallel dilatation
Serpentine/Varicose – Tortuous dilatation
Racemose/Circoid – Mass of intercommunicating small vessels

C. Based on Pathogenesis

Atherosclerotic – Most common; related to plaque buildup
Syphilitic (Luetic) – Tertiary syphilis affecting thoracic aorta
Dissecting – Blood enters vessel wall layers
Mycotic – Due to microbial infection
Berry – Found in circle of Willis (brain base)

Atherosclerotic Aneurysms

Pathogenesis

Atherosclerosis causes medial thinning and destruction
Weakening of the wall leads to dilation

Morphologic Features

Commonly infra-renal aorta
Usually >5–6 cm, mostly fusiform
Wall with fibrous tissue; mural thrombus may be present

Effects

Rupture – Risk increases with size/duration
Compression – Can affect ureters, vertebrae
Arterial Occlusion/Thromboembolism – Common complication

Syphilitic (Luetic) Aneurysms

Pathogenesis

Seen in tertiary syphilis (~10% cases)
Inflammatory infiltrate → endarteritis obliterans → media damage

Morphologic Features

Affects ascending aorta/aortic arch
Saccular aneurysms, 3–5 cm
Tree-bark intimal appearance
May cause ‘cor bovinum’ from LV hypertrophy

Effects

Rupture – Fatal hemorrhage into body cavities
Compression – Dysphagia, hoarseness, bone erosion
Cardiac Dysfunction – Aortic incompetence, coronary narrowing

Dissecting Aneurysms (Dissecting Hematoma)

Pathogenesis

Media weakening is key cause
Initiated by intimal tear or vasa vasorum hemorrhage
Risk factors:

Hypertension (90% cases)
Marfan’s syndrome
Iatrogenic trauma
Pregnancy

🩸 VEINS – NORMAL STRUCTURE

Vein walls are thinner than arteries.
Elastic tissue is scanty; no clear elastic laminae.
Sparse smooth muscle; collagen-rich media.
Valves prevent backflow—best developed in leg veins.

🪢 VARICOSITIES

Abnormally dilated & twisted veins.
Common Locations:
- Legs → Varicose veins
- Esophagus → Esophageal varices
- Anus → Hemorrhoids
- Spermatic cord → Varicocele

🧵 VARICOSE VEINS

Definition: Permanently dilated, tortuous superficial leg veins.
Peak: 40s–50s
More common in women (especially during pregnancy)
Causes:
- Genetic weakness of valves/walls
- Prolonged standing (e.g., nurses, surgeons)
- Pregnancy (compression on iliac veins)
- Hormonal effects
- Obesity
- Constipation
Pathology:
- Dilated, nodular veins
- Fibromuscular wall thickening
- Elastic degeneration, thrombosis
Effects:
- Venous stasis → congestion, edema
- Thrombosis, dermatitis, cellulitis
- Chronic varicose ulcers

🧬 PHLEBOTHROMBOSIS & THROMBOPHLEBITIS

Phlebothrombosis: Clot in vein
Thrombophlebitis: Inflammation of vein
Causes (Virchow's Triad):
- Endothelial injury
- Hypercoagulability
- Venous stasis
Risk Factors:
- Heart failure
- Cancer
- Estrogens
- Post-surgery
- Immobility

MORPHOLOGY

Gross: Normal or distended veins with thrombus
Histology: Intimal inflammation → fibroblast response → fibrosis or resolution

CLINICAL EFFECTS

Local: Swelling, pain, redness, heat
Systemic:
- Pulmonary embolism (most common)
- Septic emboli to brain/liver/meninges