Last updated: 8/10/2021 Prepared by Kurt Schaberg

Vascular Diseases
Vasculitis Inflammation of the blood vessel walls.
Can be infectious or non-infectious.
Clinical findings are diverse and depend on the organ(s) involved.
Generally have constitutional symptoms (fever, myalgias, malaise), +/- localized tissue damage due to
ischemia or bleeding (leading to single or multiorgan dysfunction). Elevated CRP and ESR.
Classified mostly based on this size of the vessel usually involved and the organs involved.
Many systemic rheumatologic diseases (e.g., Rheumatoid arthritis, sarcoidosis, and Systemic Lupus
Erythematosus) can have associated vasculitis.

Main immunological mechanisms of Non-infectious vasculitis:

1) Immune Complex-associated Vasculitis—Antigen-antibody/complement complexes deposit in the
vessel wall→ recruit inflammatory cells. Seen with many systemic immunological conditions (e.g., SLE),
drug hypersensitivity, and viral infections.

2) Antineutrophil Cytoplasmic Antibodies (ANCA) —Antibodies react with neutrophil cytoplasmic

antigens (ANCAs)→ activate neutrophils → degranulate → damages vessels.
2 types of ANCA: MPO-ANCA (formerly p-ANCA) seen with microscopic polyangiitis and Churg-Strauss,
and PR3-ANCA (formerly c-ANCA) seen in Wegner’s.

3) Anti-endothelial Cell Antibodies — Antibodies to endothelial cells

Variable Vessels
Behςet’s disease
Cogan’s syndrome

Small Vessels
Immune complex
IgA vasculitis (Henoch-Schönlein purpura)
Medium Vessels Cryoglobulin vasculitis, SLE, Goodpasture disease
Immune complex ANCA
Large Vessels
Polyarteritis nodosa Microscopic polyangiitis
Granulomatous
Giant-cell arteritis Anti-endothelial cell Granulomatosis with polyangiitis (Wegner’s)
Takayasu arteritis Kawasaki disease Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Capillaries only
Anti-endothelial cell
Anti-GBM disease Based on the Chapel Hill Consensus Conference of 2012
 Large Vessel Vasculitis
Involves large vessels (not inside of organs) with some medium-sized vessels
Histologically see lymphohistiocytic inflammation of vessel wall with frequent granulomas/giant cells.
Fragmentation of internal elastic lamina (IEL; best seen on EVG stain)
Patchy→ so get lots of levels and an EVG in biopsies. Nodular thickening of intima with medial scarring.

Takayasu Arteritis
Predominantly impacts aorta (particularly the arch)
and its major branches
Onset usually before age 50
Transmural fibrous thickening of aorta, with lumen
narrowing, particularly of branching vessels→ loss of
pulses in upper extremities.
Giant cell (Temporal) Arteritis
Usually impacts aorta and/or its major branches,
with a predilection for the branches of the carotid
and vertebral arteries, especially the temporal artery
Onset usually after age 50.
Most common vasculitis in elderly in US.
Often associated with polymyalgia rheumatica
Involvement of ophthalmic artery can cause
permanent blindness, so considered a medical Normal IEL
emergency requiring prompt Dx and treatment with
corticosteroids.
As these processes are histologically
indistinguishable, they are often identified clinically,
primarily by age. IEL fragmentation

Medium Vessel Vasculitis

Involves main visceral arteries and their branches.
Inflammatory aneurysms and stenoses are common.
Polyarteritis Nodosa (PAN)
Transmural necrotizing arteritis of medium or small arteries
(without glomerulonephritis or vasculitis of arterioles, capillaries, or
venules) with mixed inflammation, fibrinoid necrosis, and
thrombosis. Frequently involves renal artery and GI tract.
Often patchy/segmental.
Immune complex mediated.
~30% have chronic Hepatitis B
Kawasaki Disease (“Mucocutaneous lymph node syndrome”)
Arteritis impacts medium and small arteries.
Usually < 4 years old, presenting with oral, conjunctival and
palmoplantar erythema (“strawberry tongue”) with a desquamative
rash and cervical lymphadenopathy. Often post-infectious.
Predominantly coronary arteries involved→ aneurysms & MI.
Autoantibodies to endothelial/smooth muscle cells.
Treat with IVIG and aspirin.
 Small Vessel Vasculitis
Often neutrophil-predominant and leukocytoclastic→
fibrinoid necrosis, thrombosis, RBC extravasation.
ANCA-mediated
Microscopic Polyangiitis (MPA)
Necrotizing vasculitis of small/medium vessels.
Mixed inflammation with fibrinoid necrosis
Very commonly involves kidney and lung.
MPO-ANCA usually positive.

Granulomatosis with Polyangiitis (Wegner’s)

Necrotizing granulomatous inflammation.
Commonly impacts lung, nasal cavity, and kidney.
In lung/head see granulomas with geographic central
necrosis and associated vasculitis→ form ulcers and
nodules. In kidney can see crescentic glomerulonephritis.
PR3-ANCA positive.

Eosinophilic Granulomatosis with Polyangiitis

(Churg-Strauss)
Eosinophil-rich and necrotizing granulomatous
inflammation. Often impacts the lung. Associated with
asthma and eosinophilia. MPO-ANCA usually positive.

Immune complex-mediated
IgA Vasculitis (Henoch-Schönlein purpura)
Vasculitis with IgA1-dominiant immune deposits.
Often involves skin (palpable purpura), GI tract
(abdominal pain), kidney, and joints (arthritis).
Most common systemic vasculitis in kids. Usually self-
limited and post-infectious (often after URI).

Cryoglobulinemic Vasculitis
Serum cryoglobulins (Ig that precipitate out of solution at
< 37°C)→ vessel deposits→ vasculitis. Often involves
skin, kidney, and peripheral nerves. Highly associated
with Hep C and monoclonal gammopathy.

Hypocomplementemic Urticarial Vasculitis

(Anti-C1q)
Associated with anti-C1q antibodies. Immune complex→
activate complement cascade→ mast cell degranulation
and neutrophil activation→ urticaria and small vessel
vasculitis

Anti-Endothelial Cell Antibody-mediated

Anti-Glomerular Basement Membrane (GBM)
Disease (Goodpasture Syndrome)
Impacts capillaries in kidney, lung, or both. In lung→
hemorrhage. In kidney→ crescentic glomerulonephritis.
 Variable Vessel Vasculitis
Behςet’s Disease
Vasculitis involving arteries or veins of any size.
Recurrent oral and/or genital aphthous ulcers, accompanied by cutaneous, ocular, articular, GI, and/or
CNS lesions. Can get thrombosis or aneurysms.
Most common along “ancient silk road” (Middle East→ Asia)
Cogan’s Syndrome
Systemic vasculitis with predominantly ocular and inner ear findings. May also involve aorta & heart.

Infectious Vasculitis
Most often due direct extension of infected tissue. Can cause aneurysms→ “Mycotic” aneurysms
Examples where vasculitis is an important component of disease:
Syphilis→ luminal obstruction and perivascular infiltrate of lymphocytes and plasma cells.
Fungi→ Aspergillus and Mucor can cause disseminated infection with angioinvasion. Usually
immunocompromised patients. Causes obstruction→ tissue necrosis.
Other examples: Rocky mountain spotted fever, Q fever, Typhus, Meningococcus, Lyme disease

IgG4-related Aortitis/Periaortitis
Characteristic findings in adventitia: 1) Dense
lymphoplasmacytic infiltrate, 2) Storiform-type fibrosis,
3) Obliterative phlebitis.
Must see >50 IgG4-positive plasma cells in a single HPF.
Most often older men.

Coagulopathic Disorders Look for “bland” (non-inflamed) thrombi in vessels

Disseminated Intravascular Coagulation (DIC)—Consumptive

coagulopathy where systemic activation of the coagulation cascade leads
to thrombosis of small vessels throughout the body (and also bleeding).
Can occur in many settings (e.g., sepsis, trauma, etc…). See fibrin thrombi
in small vessels.
Thrombotic Thrombocytopenic Purpura (TTP)—thrombotic
microangiopathy with widespread platelet thrombi in small vessels→
hemolytic anemia, purpura, thrombocytopenia, renal dysfunction. Results
from ADAMTS13 deficiency. See platelet-rich occlusive thrombi.
Hemolytic Uremic Syndrome (HUS)—Similar to TTP (thrombotic
microangiopathy), but thrombi mostly limited to kidneys. Usually in Kids
after eating E. Coli O157:H7 (makes Shiga-like toxin toxic to endothelial
cells), which also causes bloody diarrhea.
Heparin Induced Thrombocytopenia (HIT)—antibodies recognize heparin
+ platelet factor 4 complexes→ activate platelets→ thrombocytopenia and
thrombus formation. Usually thrombi are in large vessels (e.g., DVT→ PE).
 Vascular Deposition Disorders H&E Congo
Red
Amyloidosis
Deposits of abnormally folded protein (rich in β-
sheets) in vessels and tissues→ obstructs flow and
makes rigid (impaired vasoreactivity) → ischemic
injury; Also make vessel brittle→ hemorrhage.
Extracellular eosinophilic amorphous material (H&E)
Congo Red Stain → “Apple green” birefringence
Trichrome → greyish (vs Fibrosis→ bright blue)
Can subtype (see below) to determine etiology using
IF, Mass spectrometry, immunoblotting, IHC, etc…
Category Associated Disease Amyloid Protein Precursor Protein
Systemic Amyloidosis
Plasma cell dyscrasia (1°) Multiple myeloma AL Immunoglobulin light
chain (usually λ)
Reactive systemic Chronic inflammatory conditions AA SAA
amyloidosis (2°)
Hemodialysis-associated Chronic Renal Failure Aβ2m Β2-microglobluin
Localized Amyloidosis
Senile Cerebral Alzheimer disease Ab APP
Endocrine Type 2 Diabetes AIAPP Islet amyloid peptide
Medullary thyroid CA A Cal Calcitonin
Isolated atrial AANF ANP
Hereditary
Familial Mediterranean AA SAA
Fever
Familial amyloidotic ATTR Transthyretin
neuropathy
Systemic Senile ATTR Transthyretin
Modified from: Robbins and Cotran’s Pathologic Basis of Disease,

Vascular Calcification (Mönckeberg’s Arteriosclerosis)

Calcification of arterial media layer.
Common and often incidental in older patients.
Associated with age, diabetes, renal failure, and
hyperparathyroidism.

Note: Calcification of the intima (and subsequently the

media) is very common in Atherosclerosis (discussed
separately)
 Other Deposition Disorders
Light-Chain Deposition Disease—Immunoglobulin light chains deposit in tissue in non-amyloid
form. Seen with immunoglobulin-producing neoplasms. Looks similar to amyloid on H&E, but not
Congo red positive with Apple-green birefringence. Often due to κ light chains.

Calciphylaxis—progressive skin necrosis due to calcification of small and medium-sized vessels.

Usually a result of hyperparathyroidism seen with chronic renal failure. Also see thrombi, soft tissue
calcifications, panniculitis, necrosis, and ulceration.

Oxalosis– Deposition of calcium oxalate crystals in vessels and tissues→ occlude lumen→
ischemia. Can be 1° (due to enzyme deficiency) or 2° (due to ingestion of oxalates or ethylene
glycol—antifreeze!). Birefringent crystals associated with foreign body giant cell reaction.

Common Aging-associated Disorders

Atherosclerosis
Development of atheromatous plaques in arteries.
Often most noteworthy in coronary arteries→ Myocardial
infarction or cerebral arteries→ Stroke.
Can also cause peripheral vascular disease.
Endothelial injury/inflammation → accumulation of lipoproteins
→ ingested by macrophages → foamy macrophages in intima
(“Xanthoma”) with a fibrous cap, calcifications, and smooth
muscle proliferation → gradually grows and narrows lumen →
can rupture → triggers thrombosis of rest of lumen → ischemia
→ infarction
Risk factors: obesity, diabetes, smoking, hypercholesterolemia,
men, hypertension, inflammation

Hypertensive Changes
Most commonly associated changes with “Benign” hypertension
(but also generally seen with aging!).
1) Intimal fibroplasia of small arteries (Arteriolosclerosis)
Deposition of collagenous extracellular matrix and vascular
smooth muscle cell growth between endothelium and IEL →
thickening of intima → narrowing of vessel lumen
2) Hyalinization of arterioles (Hyalinosis)
Amorphous eosinophilic material (PASd+, Congo red -) made up of
plasma proteins with matrix. Also associated with diabetes.
In “malignant” hypertension→ see hyperplastic arteriolosclerosis
→ small arteries have thickened “onion skin-like” intima
(concentric layers) with fibrinoid necrosis and thrombosis.
Intimal Proliferative Disorders
Expansion of intima by smooth muscle cells and myofibroblasts. This is a common consequence of
vascular injury and vascular activation (i.e., a common endpoint of many diseases).

Hypothenar Hammer Syndrome

Direct mechanical injury of superficial vessels
(classically of ulnar artery on hypothenar surface of
hand from overuse of a hammer)
→Lumina occlusion/thrombosis with scarring and
ingrowth of capillaries into the media
→ Present with signs of vascular insufficiency (e.g.,
cold pale or cyanotic hand)
PMID: 23887165

Moyamoya Disease
Most common in Japan. Idiopathic. Multiple spontaneous occlusions of cerebral arteries.
Secondary development of adjacent net-like systems of collaterals→ Looks like a “puff of smoke” on
angiography → can rupture → stroke

Arterial Dissections
Disruption of vessel lumen→ blood can enter “false lumen” and dissect between layers or rupture.
Frequently caused by trauma, but can be sporadic.
Common sites:
Cervical (carotid/vertebral arteries): Often younger adults.
Coronary arteries
Aorta: Often older males with history of hypertension. Also False
associated with Marfan Syndrome and bicuspid aortic valve. lumen
Stanford Type A: involves ascending aorta (more common).
Stanford Type B: only descending aorta.
With sporadic cases, microscopically often see “Cystic
Medial Degeneration” with 1)Marked loss of elastic
lamellae (best seen with elastic stain) and 2)Deposition of
proteoglycans (best seen with colloidal iron stain)

Proteoglycan accumulation

Normal elastic layers

Loss of
elastic layers

EVG stain Colloidal Iron

 Miscellaneous Disorders
Fibromuscular Dysplasia
Replacement of normal component (usually smooth
muscle) by loose fibrous tissue → causes narrowing
and weakening/aneurysm formation (like beads on a
string).
Often involves large to medium-sized blood vessels,
especially renal arteries (causing hypertension due to
renin/angiotensin system). Often middle-aged
women.

Thromboangiitis Obliterans aka “Buerger disease”

Almost exclusively in middle-aged males who are heavy smokers.
(Thought to be a pathologic response to smoking)
Acute thrombosis of peripheral vessels→ invokes inflammatory response (not a true vasculitis, IEL intact)

Angiodysplasia of the Gastrointestinal Tract

Arteriovenous malformation, often in the cecum of elderly patients.
Causes GI bleed. Thought to be degenerative.
Dilated capillaries and veins in submucosa/mucosa.
Sometimes called “vascular ectasia.”

Cerebral Aneurysms aka “Berry Aneurysm”

Saccular aneurysm from localized structural degeneration
(loss of IEL and muscle layers)
Typically occur in circle of Willis
Relatively common (~5% of population)
Associated with connective tissue disorders, polycystic
kidney disease, hypertension, etc…
→ rupture→ subarachnoid hemorrhage
PMID: 30760624

Aortic Aneurysms
Abdominal Aortic Aneurysm (AAA): Associated with atherosclerosis. Most common in older, male
smokers (screen this population with ultrasound). Often just above bifurcation with plaque, thinned
media, and bland, laminated mural thrombus. If rupture→ massive fatal hemorrhage (risk is
proportional to size).

Thoracic Aortic Aneurysm: Usually associated with hypertension (and sometimes Marfan syndrome).
As dilates→ encroaches on nearby structures (harder to swallow/breathe) and leads to aortic valve
insufficiency. Can rupture→ massive hemorrhage
 Idiopathic Myointimal Hyperplasia of Mesenteric Veins
Rare.
Usually young to middle-aged men with GI pain
and/or bleeding. Most common in left colon.
Can clinically look like IBD.

On resection: mural mesenteric veins have

concentric proliferation of smooth muscle cells in
the intima and media. (Arteries normal)

On biopsy: Arteriolized capillaries, subendothelial

fibrin deposits, fibrin thrombi, and perivascular
hyalinization. Reactive epithelium (mucin-depleted).
+/- usual ischemic changes.

Enterocolic phlebitis
Localized lymphocytic perivenular circumferential cuff of
inflammation → venous engorgement, hemorrhage, and necrosis.
Usually right-sided in middle-aged or elderly.
Can be necrotizing and/or granulomatous.