IMHO, one of the most logical and clear, of all chapters!
Aorta (elastic artery), artery, vein, capillary: Know all the differentiating histologic features
Two types of vascular diseases: Atherosclerosis Everything else
Please note that the “NONSPECIFIC” reactions to injury, are very closely paralleling the process we call “atherosclerosis”, also note that these processes seem to be more typical of arteries rather than veins.
Prostacyclin INHIBITS platelet activation, Thrombomodulin inhibits thrombin, Heparin is body’s main anticoagulant, Plasminogen, precursor of plasmin dissolves fibrin!
Because of the simple geometric fact that smooth muscle cells are arranges axially (opposite) to the axis of the blood vessel, constriction of the smooth muscle cell results in constriction of the vessel. PDGF plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis Endothelins are 21-amino acid vasoconstricting peptides produced primarily in the endothelium having a key role in vascular homeostasis. HS binds to a variety of protein ligands and regulates a wide variety of biological activities, including developmental processes, angiogenesis, blood coagulation and tumor metastasis. Nitric oxide, known as the 'endothelium-derived relaxing factor', or 'EDRF‘
Intimal thickening is a NON-specific response to vascular (chiefly arterial) injury, and is they KEY feature in atherosclerosis as well. This is logical because almost all of the vessel injuring factors come from the LUMEN of the vessel.
A-V fistulas are also called A-V malformations.
Atherosclerosis and arteriosclerosis are often used so interchangeably, it is hardly worth differentiating them anymore, other than to know they are different!
Classical features of all diseases as defined in chapter 1.
Note that there is nothing listed as “CAUSE”
In this case, the “Natural History” is very similar, if not identical, to the concept of “Pathogenesis”.
Atherosclerosis is a LIFELONG, even childhood, process. This chart is worth knowing.
Fatty STREAKS can be SEEN as YELLOW, but NOT palpated, ATHEROMAS can be palpated, thrombi are symptomatic often. A rule of thumb is that stenosis is symptomatic if > 90%.
These are also, generally, in order of severity. * Do you think an ACUTELY or FIBROTICALLY(CHRONIC) inflamed arterial wall would be most likely to develop an aneurysm?
The streaks are more noticeable at the ostia of the aorta because that is where PRESSURE is the greatest. This simple observation makes it easier to understand the relationship between hypertension and atherosclerosis
Cholerterol (really cholesterol esters) makes macrophages “foamy” and cause “clefts” extracellularly.
These should all be household words in your vocabulary.
Also very closely related! When you cant identify a specific CAUSE, you talk about “risk factors”.
“Framingham” data. Please remember that these are the ONLY four MAJOR risk factors. If somebody tells you there is anything else which is a MAJOR risk factor, nominate that joker for a Nobel prize. Notice how many of the MAJOR risk factors are controllable?
Needle shaped washed out spaces in arteries, are cholesterol clefts, and can be nothing else, and like all other fat, yellow grossly, white microscopically.
Risk factors vs. ischemic heart disease
It is easy for a smoker to FORGET that cigarettes cause atherosclerosis. i.e., MAJOR risk factor. I hope YOU do not forget.
A major challenge is suggested here!
Homocystinuria, also known as cystathionine beta synthase deficiency or CBS deficiency, is an inherited disorder of the metabolism of the amino acid methionine, often involving cystathionine beta synthase. It is an inherited autosomal recessive disorder High levels of Lp(a) is associated with increased risk of atherosclerosis. It should be < 14 mg/dL (< 35 nmol/l)
Like the sequence of events described in acute inflammation, atherosclerosis is its own Cecil B. DeMille saga! Not only should you all be familiar with these processes, but their ORDER as well. * This may be the first (i.e., earliest) microscopic and gross finding.
A very well constructed graphic understanding of the pathogenesis of atherosclerosis. Please be expected to not only KNOW these five items, but their correct ORDER too.
A simplified (nothing is TOO or OVERLY simplified, imho) concept of atherosclerosis.
This is the VERY VERY best diagram of atherosclerosis you will ever see. The nice thing about diagrams is that you really do not have to memorize them, but just visually “recall” the concepts!
Degeneration/Neoplasm/Inflammation link! Isn’t atherosclerosis wonderful? Here we have all 3 classifications of disease in one entity----atherosclerosis!
In all honesty the correct answer is “NO”, however it can be slowed down by knowing the treatable or preventable risk factors. No doubt you will occasionally hear of AMAZING BREAKTHROUGHS, which are all claims by scammers and lunatics.
Note that classically topics of arterial diseases are divided into 1) atherosclerosis and 2) everything else.
When you think hypertension, think essential, then renal, then endocrine, then other!
Always know that hypertension can be understood best by remembering the simple BP=COxPR equation.
Sometimes this is called RAAS Renin Angiotensin (but angiotensis does SO MUCH MORE than just activate aldosterone) Aldosterone Sodium
Know ALL the ways angiotensin II increases blood pressure! Be familiar with the FIVE ways angiotensin II can INCREASE blood pressure: 1) increase sympathetic activity 2) tubular reabsorption of Na+ 3) Aldosterone secretion 4) arteriolar vasoconstriction 5) ADH secretion Chances are, every free dinner you attend with have a drug rep showing you some kind of RAAS diagram like this.
A little more thorough diagram of RAAS pathology---- genetic and acquired.
Often, benign or “malignant” hypertension is described as two different types of changes in arterioles, usually renal. Benign: Hyalization of arteriole wall Malignant: Fibrinoid necrosis and “onion skinning” of arteriole wall
Does it look like you’ve seen this somewhere before, i.e., the discussion of atherosclerosis?
Know the difference between a TRUE (endothelial expansion) and FALSE (NO endothelial expansion) aneurysm
Of course any artery with this abundance of elastic fibers would HAVE to be an aorta or an elastic artery! Imagine the wavy elastic fibers as being little rubber bands!
Specifics of thoracic aneurysms.
Dissection (i.e., blood or hemorrhage disrupting the wall of a large artery) can be both a cause or an effect of an aneurysm. Would the continued dissection of that acute hemorrhage result in, more likely, a TRUE or FALSE aneurysm?
Why are arteritides highly linked to autoimmune diseases? Answer: Because there are rarely any known causative external (i.e., infectious) pathogens, and many are associated with known auto-antibodies.
Note the disruption of the internal elastic lamina. Why?
See my clipped pic, or go to the microscope directly by clicking on the link!
Pulseless is the buzzword in this case. Why?
Nuclear “dust” from neutrophils, i.e., leukocyto”clasia” is the hallmark.
Mortality has improved significantly, but flare-ups, i.e., recurrences, are still the main concern.
Why is the “necrosis” of Wegener’s not called “caseating”? Ans: Because, by tradition, rather than objectivity or logic, “caseation” has been attributed to tuberculosis. Yes, we know this is not fair. Wegener’s is PRIMARILLY a disease of the UPPER and LOWER respiratory tracts, however, eye involvement is frequent and may range from a mild conjunctivitis to dacryocystitis, episcleritis, scleritis, granulomatous sclerouveitis, ciliary vessel vasculitis and retro‐orbital mass lesions.
What is the most unforgettable picture I remember from medical school?
Most classical systemic auto-immune diseases have an element of vasculitis. Remember the THREE magnets for Ag-Ab complexes: GBM, Synovia, and BLOOD VESSELS!!!!!
A “mycotic” aneurysm is any aneurysm that has become secondarily infected, usually by bacteria. Hence the name “mycotic” is a misnomer. Also note that aspergillis and mucormycosis were also previously mentioned as the two classic “mold” diseases of immunocompromised patients.
WHITEBLUERED is the proper order of color change.
Knowing the correct ORDER of color change, will help you diagnose it properly! WHITEBLUERED
The plural of varix is varices. Varices are generally the same as varicosities. Hemorrhoids are also varices or varicosities, but are not usually called that.
Thrombophlebitis = Phlebothrombosis
Is “dusky cyanosis” a redundant term? Probably.
All of these factors should make sense anatomically!
Recall the childhood warning.
Note the relative LACK of cellulitis, although in most cases cellulitis is present, and in the presence of cellulitis, the diagnosis of lymphangitis would usually not be hazarded.
Any imaginable type of damage to lymphatics could cause lymphedema.
Peau d’orange is classically described in INFLAMMATORY carcinoma of the breast in which dermal lymphatics are extensively plugged up by tumor nests
Blockage of the thoracic duct is the usual cause of chylothorax. If you ever aspirate white milky fluid from a chest, pericardial, or abdominal tap, I really do not think it can be anything but chyle. Whiteness is due to FFA’s.
Vascular tumors generally follow the same diagnostic patterns of other mesenchymal (i.e., “soft” tissue) tumors. Often the KEY difference is that “endothelium” lined blood filled spaces, or identification of endothelial cells by antigenic markers, such as factor VIII, is usually present.
The presence of the NUMBER of mitotic figures is a KEY feature in determining the benignity or malignancy of ANY connective tissue tumor. Most pathologists are terrified of soft tissue tumors with mitoses and/or atypia and ALWAYS seek expert opinions.
Small spaces = often small people, i.e., kids Large spaces = often large people, i.e., adults
Would a stain for Factor VIII help identify a tumor as being of vascular origin? Answer: YES Why? Because, if you remember, the coagulation Factor VIII is present in endothelial cells. Is “blanching” a most important clinical test to determine if a tumor is of blood vessel origin? Ans: YES
Almost all vascular tumors show endothelial lined spaces. If they are not apparent, a specific stain for endothelial cells, like Factor VIII is commonly ordered.
“-ectasia” is a generic term meaning dilation and is primarily used with regard to veins rather than arteries. Osler-Weber-Rendu syndrome, or hereditary hemorrhagic telangiectasia (HHT), is a rare genetically determined disorder that affects blood vessels throughout the body and results in a tendency for bleeding. HHT is an autosomal dominant disorder characterized by vascular dysplasia and hemorrhage. The prognosis for patients with the disease is good as long as bleeding is promptly recognized and adequately controlled.
Note the LACK of a malignant sounding name. Almost all malignant, or potentially metastasizable vascular tumors look alike so there is no need to try to differentiate them here microscopically.
Almost all malignant, or potentially metastasizable vascular tumors look alike so there is no need to try to differentiate them here microscopically.
*Note ALSO the lack of a malignant sounding name. Almost all malignant, or potentially metastasizable vascular tumors look alike so there is no need to try to differentiate them here microscopically. Almost all malignant, or potentially metastasizable vascular tumors look alike so there is no need to try to differentiate them here microscopically.
If you know a patient who has had an angioplasty, chances are he has had more than one.
• The sum total of all the factors and
processes involved in tissue injury
and the body’s ability to grow
vessels, develop new pathways,
and re-perfuse areas in response
to tissue and/or blood vessel
• Arteriovenous fistulas
• Also called ArterioVenous Malformation
• Common factor is abnormal communication
between high pressure arteries and low
• Usually congenital (malformation), but can
be acquired by trauma or inflammation
• Most often described in the brain as an AVM
• Often asymptomatic or with hemorrhage or
• GENERIC term for ANYTHING
which HARDENS arteries
– Atherosclerosis (99%)
– Mönckeberg medial calcific
– Arteriolosclerosis, involving small
arteries and arterioles, generally
regarded as NOT strictly being part
of atherosclerosis, but more related
to hypertension and/or diabetes
• Chiefly CHOLESTEROL,
• HDL mobilizes cholesterol FROM
atheromas to liver
• LOW CHOLESTEROL diet is GOOD
• UNSATURATED fatty acids GOOD
• Omega-3 fatty acids GOOD
• Exercise GOOD
• If there was one disease
which I could challenge you
to, as a dare, to PROVE to
me that was NOT EXACTLY
atherosclerosis, it would be
DIABETES! Any takers?
NON major factors
• Homocysteinuria/homocysteinemia, related
to low B6 and folate intake
• Coagulation defects
• Lipoprotein Lp(a), independent of
cholesterol. Lp(a) is an altered form of LDL
• Inadequate exercise, Type “A” personality,
obesity (independent of diabetes)
• Protective effect of moderate alcohol?
Medical LIE, sponsored by the booze
industry and alcoholic physicians!
• “atherosclerosis is a chronic
inflammatory response of
the arterial wall initiated by
injury to the endothelium”
Chronic endothelial injury
LDL, Cholesterol in arterial WALL
OXIDATION of lipoproteins
Monocytes migrate endothelium*
Platelet adhesion and activation
Migration of SMOOTH MUSCLE from media to
intima to activate macrophages (foam cells)
• Proliferation of SMOOTH MUSCLE and ECM
• Accumulation of lipids in cells and ECM
Main FOUR STARS of
• 1) Endothelial Injury
• 2) Inflammation
• 3) Lipids
• 4) Smooth Muscle Cells, SMCs
• Oligoclonality of cells in
• Chlamydia, CMV as
• Know what is preventable
• Know what is MAJOR (vs. minor)
• Know PRIMARY vs. SECONDARY
• Understand atherosclerosis begins in
• Risk factors in CHILDREN predict the
• Understand SEX, ETHNIC differences
If the perfusion of the
juxtaglomerular apparatus in the kidneys
decreases, then the juxtaglomerular cells
release the enzyme renin.
Renin cleaves an inactive peptide called
angiotensinogen, converting it into
Angiotensin I is then converted to angiotensin
II by angiotensin-converting enzyme (ACE),
which is found mainly in lung capillaries.
Angiotensin II is the major bioactive product of
the renin-angiotensin system. Angiotensin II
acts as an endocrine, autocrine/ paracrine, and
• Chiefly arterial
• Infectious (5%) vs. Non-infectious (95%)
• NON-infectious are generally “AUTO”IMMUNE. Why?
• Persistent findings:
– Immune complexes
– ANTI-NEUTROPHIL AB’s (Wegener’s, “Temporal”)
– ANTI-ENDOTHELIAL CELL AB’s (Kawasaki)
• Often DRUG related (Hypersensitivity, e.g.),
especially small blood vessels.
aka, Giant Cell Arteritis, GCA
• ADULTS, older
• Mainly arteries of the head and
temporal arteries are the most visibly,
palpably, and surgically accessible
• BLINDNESS most feared sequelae
• GRANULOMATOUS WALL
• OFTEN associated with marked ESR
elevation to be then known as
• Anti-NEUTROPHIL AB’s often POSITIVE
• Involves aortic arch and other heavilly
elastic arteries, i.e., chief thoracic
aorta branches, most commonly young
• FEMALES <40
• “PULSELESS” disease
• NECROSIS, Giant Cells also
ANY MEDIUM or SMALL artery
OFTEN visceral arteries
Infarcts, aneurysms, ischemia
CLASSICAL AUTOIMMUNE disease
NECROTIZING (fibrinoid) inflammation
• Sometimes anti-neutrophil antibodies,
especially in the smaller vessel diseases
• One of the CLASSICAL systemic autoimmune diseases, like SLE, RA, or SS
• CHILDREN <4
• CORONARY ARTERIES
• LEADING cause of ACQUIRED heart
disease in children
• USA and JAPAN
• Fatal in only 1%
• Red tongue, adenopathy
• Anti-endothelial cell ABs
• SMALL VESSELS OF ALL TYPES,
e.g., capillaries and veins too
• FRAGMENTED NEUTROPHILS
• aka, LEUKOCYTOCLASIA
• aka, NUCLEAR “DUST”
• Most are ALLERGIC reactions to
allergens like penicillin or strep
• DERMATOLOGIST’s DISEASE
• M>F, often in 40’s
• ACUTE NECROTIZING GRANULOMAS OF UPPER
an LOWER respiratory tract
• NECROTIZING GRANULOMATOUS VASCULITIS
of SMALL vessels of ALL types
• Often renal involvement, “crescentic”
• ANTI-NEUTROPHIL-CYTOPLASMIC-AB’s (ANCA)
• 100% caused by cigarette smoking
• MEN>>>F, 30’s, 40’s
• Often arteries are 100% obliterated,
hence the name “obliterans”
• EXTREMITIES most often involved
• PRIMARY: (formerly Raynaud “DISEASE”)
Vasoconstriction usually triggered by COLD, emotion
Can be tip of nose, not only digits
Self Limited, Gangrene UN-common
Arteries often do NOT show diagnostic pathology
• SECONDARY: (formerly Raynaud “Phenomen.”)
– Buerger Disease
• 20% of population, F>M
• Related to increased venous pressure, age, valve
• Superficial veins of lower extremities most
• PATH: 1) DILATED, 2) TORTUOUS, 3) ELONGATED,
4) SCARRED (phlebosclerosis), 5) CALCIFICATIONS,
6) NON-UNIFORM SMOOTH MUSCLE
• Conceptually like varices or hemorrhoids
• “Phlebosclerosis” is what your pathologist will
• 90% DEEP veins of the legs
• IDENTICAL to PHLEBOTHROMBOSIS
• Factors: CHF, Neoplasia (esp. GI, panc.
Lung adenocarcinomas “migratory”
thrombophlebitis), pregnancy, obesity,
post-op, immobilization, or any of the
parts of Virchow’s triangle
• Sequelae: PE most feared
• Symptoms: edema, cyanosis, heat, pain,
tenderness, but usually……..NONE!!!
• Usually from bronchogenic CA
or mediastinal lymphoma
• “DUSKY CYANOSIS” of:
• Secondary to:
– NEOPLASMS (external compression)
– ASCENDING THROMBOSIS from
– AAA, Gravid uterus
• Bilateral leg edema
• Massive proteinuria if renal veins
involved (like nephrotic syndrome)
• From regional infections
• Group-A beta-hemolytic strep most
• Lymphatics dilated, filled with WBCs
• Cellulitis usually present too
• Lymphadenitis also usually follows
• If lymph nodes cannot filter (process)
antigens enough septicemia
• Lymphatic channels blocked or
scarred or absent:
– Post surgical
– Post radiation
– Tumoral (peau d’orange- breast)
• BENIGN (NEVER metastasize, in fact
some are not even TRUE neoplasms,
• INTERMEDIATE (rarely metastasize)
• MALIGNANT (FREQUENT and EARLY
metastases, like any other sarcoma
Rare mitosis--------------------------Common mitosis
Mild, rare atypia------------Frequent, severe atypia
NO mets----------------------------Early, frequent
• Often a generic term for ANY benign blood
• CAPILLARY (small vascular spaces)
– Also called “juvenile”, often called “birth marks”
– Usually regress with age
• CAVERNOUS (LARGE vascular
– Also called “adult”
– Usually do NOT regress
• ORAL CAVITY MOST COMMON
• Histology like capillary
• Indistinguishable from normal
Small 1-2 mm
90% Head and neck region in kids <2
When large size and/or spaces
present often called “CYSTIC
• 1 cm
• Most commonly under nail
MISC. “BENIGN” TUMORS
• -ectasias, telangiectasias
• Nevus Flammeus, aka, port wine stain----
• Spiders (spider telangiectasias), ass. W.
• Osler-Weber-Rendu Disease (Hereditary
• Bacillary Angiomatosis, in HIV patients,
caused by bacilli of Bartinella species
• Kaposi Sarcoma, KS
– 1) Classic European, described 1872, NON-HIV
– 2) African, pre-HIV, now HIV- and HIV+
– 3) Transplant associated, HIV– 4) AIDS KS, caused by HHV-8, aka KSHV
– PATCH PLAQUENODULE
(HETEROGENEOUS GROUP OF
Diagnosis of vascular neoplasms may require
the use of endothelial cell markers such as
Factor VIII or CD-31, especially if clear cut
vascular spaces are difficult to see, especially if
the tumor is UNDIFFERENTIATED enough to the
degree that endothelial lined spaces are NOT
May not look “vascular” at all
Frequent and often bizarre mitoses
Behave as any sarcoma might, i.e., early
– HETEROGENOUS group of disorders
– Most commonly arising in pelvic retroperitoneum
• Metallic mesh
• Permanently placed
• Stays patent longer
• OFTEN DRUG COATED
– Prevent thrombosis
– Prevent spasm
– Delay RE-stenosis
• 400,000 CABG grafts per year in USA
• Saphenous v. vs. Internal mammary a. (internal
• 50% patent after 10 years, for saphenous v.
• 90% patent after 10 years, for mammary a.
• Endothelial and smooth muscle migration and
proliferation are key factors for success