VASCULAR PATHOLOGY

(PEMBULUH DARAH)
CANGARA, M. HUSNI, MD,
PhD

STRUKTUR & FUNGSI

Dinding arteri >> tebal dibanding

vena
Ada 3 lapisan : intima, media,
adventitia. Lebih jelas di pemb. darah
besar spt arteri.
Intima : selapis sel endotel dgn jar.
Ikat sub-endotel yg minimal.
Lamina elastic interna memisahkan
tunica intima dgn tun. media

STRUKTUR & FUNGSI

Tunica media

Lapisan dalam : O2 & nutrient dari lumen

secara difusi by memb. elastica int.
Lapisan luar : by Vasa vasorum
Tunica adventitia
Lapisan terluar (jar. Ikat, serabut saraf, &
vasa vasorum),
Tipe Arteri (ukuran & struktur):
a. besar/elastica, a. sedang/muskular, a.
kecil & arteriolar.

STRUKTUR & FUNGSI

Arteri besar kaya serat elastis (tunica

media)
aorta mengembang (sistole),
kempes (diastole)

Arteri sedang & arteriolar : kontraksi sel

otot polos (vasokonstriksi), relaksasi

(vasodilatasi)
diameter lumen berubah
aliran drh & tek. drh

Kapiler : spt diameter eritrosit (7-8m), tdk

ada tunica media.

STRUKTUR & FUNGSI

Kapiler : dinding tipis & aliran lambat; tempat

pertukaran zat2 antara darah & jaringan.

Post capiler venula : kebocoran vaskular &

eksudasi lekosit >> (proses inflamasi)

Vena : diameter & lumen>>, dinding lebih

tipis & krg terorganisasi

dilatasi
irreguler, kompressi, mudah ditembus sel
tumor & radang.

Sal. Limfe : dinding tipis, dilapisi endotel, sist.

draignase utk cairan interstitial & sel radang,

transpor bakteri & sel tumor

Pembentukan pembuluh darah

Vasculogenesis : pembentukan pembuluh

darah selama embriogenesis

Angiogenesis (neovaskularisasi) : proses

pembentukan pembuluh darah pada

organisme dewasa.

Arteriogenesis : remodeling arteri yg

sudah ada sebagai respon terhadap

perubahan kronik pada tekanan atau aliran
darah.

Kelainan kongenital
Developmental/berry aneurysma : di

cerebral vascular
ruptur,
perdarahan intracerebral

Arteriovenous fistula : hub. Langsung

antara arteri & vena, tanpa melalui kapiler

Fibromuscular dysplasia : penebalan yg

iregular, fokal dinding arteri medium &

besar

Respon sel endotel terhadap

jejas
Aktivasi endotel : respon sel endotel

terhadap stimulus dgn mengatur fungsinya

& mekspresikan sifat2 barunya.

Disfungsi endotel : perubahan fenotip yg

menginduksi permukaan endotel menjadi

trombogenik, adhesiv thd sel2 radang

Endotel mempengaruhi sel otot polos

melalui produksi NO (relaksasi) & endotelin

(kontraksi)

Endothelial cell responses to environmental stimuli. Certain cues (e.g., laminar flow and constant
growth factor levels) lead to stable endothelial cell activation that maintains a nonthrombotic interface
with appropriate smooth muscle cell tone. Pathologic mediators or excessive stimulation by normal
physiologic pathways (e.g., increased inflammatory cytokines) can result in endothelial cell
dysfunction. VEGF, vascular endothelial growth factor.

Respon sel otot polos vaskular

terhadap jejas
Sel otot polos memiliki kemampuan untuk

berproliferasi ketika dirangsang.

Sel otot polos dapat mensintesa kolagen,

elastin dan proteoglikan matriks ekstra

seluler dan menghasilkan growth factors dan
sitokin.

Penebalan tunica intima

Jejas vaskular (endotel hilang atau disfungsi)

proliferasi sel otot polos

intima menebal

sintesa matriks

pembentukan neointima.

Sel otot polos & prekursornya bermigrasi ke

intima, proliferasi dan sintesa ECM.

Penebalan intima

penyempitan/stenosis
pemb. Darah kecil dan medium,mhambat
perfusi jaringan

Proses ini dpt terjadi pada proses penuaan

(normal)

Hipertensive vascular disease

National Heart, Lung and Blood Institute USA :

tek. diastole (> 89)& sistole (>139) yg menetap

resiko atherosclerosis & gejala hipertensi.

95% hipertensi: idiopatik (essential hipertensi),

tdk menyebabkan ggn dalam jangka pendek.

Hipertensi malignant (accelerated) :

hipertensi berat (sistole > 200, diastole> 120);

ggl ginjal; perdarahan & eksudasi retina dengan
atau tanpa papiledema.

Regulasi tekanan darah

Tek. Darah adl. Fungsi dari cardiac output (CO) &

resistensi vaskular perifer.

CO sgt bergantung pd volume darah, dipengaruhi

keseimbangan Natrium.

Resistensi vasc. perifer ditentukan oleh level arterioles

& dipengaruhi faktor saraf , hormonal.

Peranan ginjal :

- sistem renin angiotensin

- produksi subtansi relaksasi, antihipertensi
- reabsorbsi natrium

oleh tubulus proximal

- natriuretic factor (atrial/ ventrikel) : reabsorbsi Na

Blood pressure regulation. A,

The critical roles played by
cardiac output and peripheral
resistance in modulating
blood pressure. B, Interplay
of renin-angiotensinaldosterone and atrial
natriuretic peptide in
maintaining blood pressure
homeostasis.

Mekanisme hipertensi esensial

Dipengaruhi faktor genetik, bersifat jarang
Kelainan gen tunggal :

- kelainan gen enzim untuk metabolisme aldosteron

- mutasi protein yg mempengaruhi reabsorbsi
natrium
Eksresi Na

volume cairan &CO ; vasokontriksi

tekanan darah
Vasokontriksi

resistensi perifer

tek. drh

Faktor lingkungan mempengaruhi fak. genetik

HIPERTENSI SEKUNDER
5 10 %

DARI SEMUA
HIPERTENSI

Kelainan vaskular pd hipertensi

Hyaline arteriosclerosis : penebalan hialin

merah mudah, homogen + penyempitan lumen

*kebocoran protein plasma melalui sel endotel yg
rusak & sintesis matriks sel otot polos
*dpt ditemukan pd org tua, diabetic mikroangiopati, nephrosclerosis

Hyperplastic arteriosclerosis : penebalan

dinding yg blapis2 & lumen sempit (onion skin
lesions).
* penebalan sel otot polos, reduplikasi membran
basalis.

Vascular pathology in hypertension. A, Hyaline arteriolosclerosis. The

arteriolar wall is thickened with increased protein deposition (hyalinized), and
the lumen is markedly narrowed. B, Hyperplastic arteriolosclerosis (onionskinning; arrow) causing lumenal obliteration (arrow; periodic acid-Schiff
stain).

Atherosclerosis
Lesi intima berupa atheroma yg menonjol ke lumen

pembuluh darah

Plak atheroma:

lesi menonjol berisi inti lemak (kolesterol, kolesterol

ester) kuning, lunak yg dilapisi selaput fibrous putih.

Plak menybbkan obstruksi aliran darah, ruptur

hingga terjadi trombosis, melemahkan tunika media

terjadi aneurisma.

Atherosclerosis menyebabkan morbiditas &

mortalitas yg tinggi

The major components of a well-developed intimal

atheromatous plaque overlying an intact media.

Epidemiologi Atherosclerosis

Faktor resiko yg tdk dapat dimodifikasi

- usia; bermanifestasi pd usia pertengahan ke atas, usia

40-60 thn insidens infark miokard 5 X
- jenis kelamin;
*wanita premenopause relatif aman thd atherosclerosis
(bila hipertensi, diabetes, hipelipidemia tdk ada)
*post menopause insidens pd wanita meningkat (faktor
estrogen protektif)
- genetik; familial hypercholesterolemia

Faktor yg dpt dimodifikasi

Hiperlipidemia (hipercolesterolemia)

*LDL (bad) cholesterol

bentuk kolesterol yg dibawa ke jar. perifer
*HDL (good) cholesterol , memobilisasi kolesterol dari
jar ke hati utk dieksresi ke empedu.
*intake kolesterol & saturated fats : cholesterol
ex. kuning telur, lemak hewani, mentega
*diet kolesterol , tinggi poly unsaturated fats
cholesterol , ex omega 3 (fish oil)

Faktor yg dpt dimodifikasi

Hipertensi : sistole & diastole

penybb utama hipertrofi ventrikel kiri

Merokok
Diabetes mellitus menginduksi

hiperkolesterolemia

Faktor2 lainnya
Inflamasi : C-reaktive protein (CRP) marker

CRP disekresikan oleh sel2 dlm intima atherosclerotic, utk

mengaktifkan sel endotel menjadi pro-trombotic state &
daya adhesive endotel thd lekosit.
Hiperhomositeinemia : ada hub. kuat dgn peny. Arteri

coroner, stroke, trombosis.

*disebabkan intake folat, vitamin B12 rendah

Sindrom metabolik : kelainan berhub. dgn resistensi

insulin. (intoleransi glukosa, hipertensi, obesitas)

dislipidemia menyebabkan disfungsi sel endotel melalui

peningkatan stress oksidatif.

Faktor2 lainnya
Lipoprotein

berhubungan dgn resiko penyakit

coroner & cerebrovascular.

Faktor2 hemostasis.
Faktor2 lain :

exercise kurang, personality

tipe A (kompetitif, stress), obesitas

Pathogenesis atherosclerosis

Jejas endotel : permeabilitas vaskular >>, adhesi

lekosit, trombosis.

Akumulasi lipoprotein : LDL & bentuk oksidasinya

Adhesi monosit ke endotel, migrasi ke intima &

transformasi ke makrofag & foam cell.

Adhesi platelet
Pelepasan mediator untuk menginduksi migrasi sel

otot polos

Proliferasi sel otot polos & produksi ECM

Akumulasi lemak extra dan intra-seluler.

Evolution of arterial wall changes in the

response to injury hypothesis. 1, Normal.
2, Endothelial injury with adhesion of
monocytes and platelets (the latter to
sites where endothelium has been lost).
3, Migration of monocytes and smooth
muscle cells into the intima. 4, Smooth
muscle cell proliferation in the intima with
ECM production. 5, Well-developed
plaque.

Hypothetical sequence of cellular interactions in atherosclerosis. Hyperlipidemia and other risk factors are thought to cause endothelial
injury, resulting in adhesion of platelets and monocytes and release of growth factors, including platelet-derived growth factor (PDGF),
which lead to smooth muscle cell migration and proliferation. Foam cells of atheromatous plaques are derived from both macrophages and
smooth muscle cells-from macrophages via the very-low-density lipoprotein (VLDL) receptor and low-density lipoprotein (LDL)
modifications recognized by scavenger receptors (e.g., oxidized LDL), and from smooth muscle cells by less certain mechanisms.
Extracellular lipid is derived from insudation from the vessel lumen, particularly in the presence of hypercholesterolemia, and also from
degenerating foam cells. Cholesterol accumulation in the plaque reflects an imbalance between influx and efflux, and high-density
lipoprotein (HDL) probably helps clear cholesterol from these accumulations. Smooth muscle cells migrate to the intima, proliferate, and
produce ECM, including collagen and proteoglycans. IL-1, interleukin-1; MCP-1, monocyte chemoattractant protein 1.

Morfologi
Fatty streaks : lesi awal pd atherosclerosis

@T.d. foam cell makrofag yg mengandung lipid

@Awal : bintik2 kuning yg banyak, datar
Bergabung menjadi lapisan panjang (> 1 cm)
@Tdk mybbkan gangguan aliran darah

Plak atherosclerotik :

Penebalan intima + akumulasi lipid di lumen arteri,

Warna putih hingga kuning diameter 0,3-1,5 cm
Bisa menjadi massa yg besar

Fatty streak, a collection of foamy macrophages in the intima. A, Aorta with fatty streaks (arrows), associated largely with the ostia of branch vessels. B,
Photomicrograph of fatty streak in an experimental hypercholesterolemic rabbit, demonstrating intimal, macrophage-derived foam cells (arrows).

Gross views of atherosclerosis in the aorta. A, Mild atherosclerosis composed of fibrous plaques, one of which is denoted by the arrow. B, Severe disease
with diffuse and complicated lesions (with plaque rupture and superimposed thrombosis), some of which have coalesced.

Histologic features of atheromatous plaque in the coronary artery. A, Overall architecture demonstrating fibrous
cap (F) and a central necrotic (largely lipid) core (C). The lumen (L) has been moderately compromised. Note that a
segment of the wall is free of plaque (arrow); the lesion is therefore "eccentric". In this section, collagen has been
stained blue (Masson's trichrome stain). B, Higher power photograph of a section of the plaque shown in A,
stained for elastin (black), demonstrating that the internal and external elastic membranes are attenuated and the
media of the artery is thinned under the most advanced plaque (arrow). C, Higher magnification photomicrograph
at the junction of the fibrous cap and core, showing scattered inflammatory cells, calcification (arrowhead) and
neovascularization (small arrows).

Atherosclerotic plaque rupture. A, Plaque rupture without superimposed thrombus, in a patient who died
suddenly. B, Acute coronary thrombosis superimposed on an atherosclerotic plaque with focal disruption of the
fibrous cap, triggering fatal myocardial infarction. In both A and B, an arrow points to the site of plaque rupture .

Akibat peny. atherosclerotic

Target utama : arteri tipe elastica & tipe muscularis
Akibat utama : infark miokard, infark cerebral/ stroke,

aneurisma aorta, ganggren kaki.

Prinsip :

*oklusi pemb drh kecil

*plak ruptur

emboli

mggu perfusi jar. distal

obstruksi vasc. distal
trombosis vasc. Akut

*kerusakan dinding pemb drh

aneurisma

Akibat peny. atherosclerotic

Atherosclerotic stenosis:

* plak menyumbat lumen vaskular scr perlahan2

mengganggu aliran darah & jejas iskemik
* 70% oklusi (a. coronaria): critical stenosis
angina pd saat beraktivitas (stable angina)
Acute plaque change:

* (1) rupture/fissuring, (2) erosion/ulceration,

(3) hemorrhage into the atheroma
* plak dgn fibrous caps tipis, <<sel otot polos,
sel inflamasi : mudah ruptur (unstable plaque).

Akibat peny. atherosclerotic

Trombosis:

partial/total trombosis akibat plak yg

rusak
sindroma coronary akut

Vasokonstriksi pd daerah atheroma

The natural history, morphologic features, main pathogenic events, and clinical
complications of atherosclerosis.

Schematic comparing vulnerable and stable atherosclerotic plaque. Whereas stable

plaques have densely collagenous and thickened fibrous caps with minimal inflammation
and negligible underlying atheromatous core, vulnerable plaques (prone to rupture) are
characterized by thin fibrous caps, large lipid cores, and increased inflammation.

Aneurisma

Dilatasi lokal pd jantung & pembuluh darah yang

abnormal. (kongenital, acquired)

1. True aneurysm: mengenai dinding jantung &

vascular yg lemah dan tipis.

Ex.
Atherosclerotic, sifilis, an. kongenital, post infark.

2. Pseudo/ false aneurysm: hematom extra-

vascular yg berhub. dgn daerah intravascular

3. Saccular aneurysm: penonjolan yg speris

4. Fusiform aneurysm: dilatasi difus,

sirkumferensial pd segment vascular

Aneurysms. A, Normal vessel. B, True aneurysm, saccular type. The wall focally bulges
outward and may be attenuated but is otherwise intact. C, True aneurysm, fusiform type.
There is circumferential dilation of the vessel, without rupture. D, False aneurysm. The
wall is ruptured, and there is a collection of blood (hematoma) that is bounded externally
by adherent extravascular tissues. E, Dissection. Blood has entered (dissected) the wall of
the vessel and separated the layers. Although this is shown as occurring through a tear in
the lumen, dissections can also occur by rupture of the vessels of the vaso vasorum
within the media.

Cystic medial degeneration. A, Cross-section of aortic media from a patient with Marfan syndrome, showing marked elastin fragmentation and formation of areas devoid
of elastin that resemble cystic spaces (asterisks). B, Normal media for comparison, showing the regular layered pattern of elastic tissue. In both A and B, elastin is
stained black.

Patogenesis aneurisma
Plak atherosclerosis menekan tunica media &

mengganggu difusi O2 & nutrient

lapisan media degenerasi & nekrosis
dinding vascular lemah

Aneurisma aorta thoracalis (hipertensi)

Penekanan pd struktur mediastinum, ggn

pernapasan, sulit menelan, batuk yg menetap
(n. laryngeus rec.), nyeri akibat erosi tulang,
penyakit jantung, ruptur.

Abdominal aortic aneurysm. A, External view, gross photograph of a large aortic aneurysm that ruptured;
the rupture site is indicated by the arrow. B, Opened view, with the location of the rupture tract indicated
by a probe. The wall of the aneurysm is exceedingly thin, and the lumen is filled by a large quantity of
layered but largely unorganized thrombus.

Aortic dissection
Darah memisahkan bidang laminar dari lapisan

media utk membentuk saluran berisi darah di

dalam dinding aorta.

Pathogenesis :

Hipertropi media vasa vasorum

degenerasi t. media aorta
hilangnya sel otot polos

Aortic dissection. A, An opened aorta with proximal dissection originating from a small, oblique intimal tear (identified by the probe), allowing blood to enter the media and
creating an intramural hematoma (narrow arrows). Note that the intimal tear has occurred in a region largely free of atherosclerotic plaque and that propagation of the
intramural hematoma is arrested at a site more distally where atherosclerosis begins (broad arrow). B, Histologic view of the dissection demonstrating an aortic intramural
hematoma (asterisk). Aortic elastic layers are black and blood is red in this section, stained with the Movat stain.

Diagrammatic representation of the typical vascular sites involved with the more common
forms of vasculitis, as well as the presumptive etiologies. Note that there is a substantial
overlap in distributions. ANCA, antineutrophil cytoplasmic antibody; SLE, systemic lupus
erythematosus.

Vasculitis

Inflamasi dinding pembuluh darah

Mekanisme :

*invasi langsung dinding vascular oleh

patogen
*reaksi imun :
- kompleks imun
- antineutrofil cytoplasmic antibody (ANCA)
- anti-endotelial cell antibody

Giant cell (temporal) arteritis

Radang kronik granulomatosa arteri kecil-

sedang (a. temporalis atau a. opthalmicus)

Pathogenesis :

respon imun seluler (sel- T) terhadap antigen yg

tdk diketahui atau kemungkinan antigen dari
dinding pembuluh darah.

Giant-cell (temporal) arteritis. A, H&E stain of section of temporal artery showing giant cells at the
degenerated internal elastic lamina in active arteritis (arrow). B, Elastic tissue stain demonstrating focal
destruction of internal elastic lamina (arrow) and intimal thickening (IT) characteristic of long-standing or
healed arteritis. C, Examination of the temporal artery of a patient with giant-cell arteritis shows a
thickened, nodular, and tender segment of a vessel on the surface of head (arrow).

Takayasu arteritis
Vasculitis granulomatosa arteri medium-besar
Ditandai gangguan penglihatan dan lemahnya

nadi pada extremitas atas (pulseless disease)

Penyebab & pathogenesis:

unknown, diduga karena reaksi imun.

Polyarteritis nodosa
Vaskulitis sistemik pada pembuluh darah

tipe muskular (kecil-sedang) spt pd renal,

visceral dan pulmonar.

Kebanyakan penyebabnya tdk diketahui

Beberapa diantaranya ada hubungan

dengan ANCA dan hepatitis B.

Wegener granulomatosis
Necrotizing vasculitis (triad) :

@Acute necrotizing granuloma sal napas

atas,bawah
@Vasculitis granuloma: vascular kecil-sedang
@Renal disease

Pathogenesis:

Rx. hipersensitif seluler (sel-T) terhadap agen2

infeksi yg diinhalasi atau dari lingkungan

Representative forms of ANCA-associated small-vessel vasculitis. A, Leukocytoclastic vasculitis

(microscopic polyangiitis) with fragmentation of neutrophils in and around blood vessel walls. B and C,
Wegener granulomatosis. B, Vasculitis of a small artery with adjacent granulomatous inflammation
including epithelioid cells and giant cells (arrows). C, Gross photo from the lung of a patient with fatal
Wegener granulomatosis, demonstrating large nodular centrally cavitating lesions.

Tromboangiitis obliterans (Buerger

disease)
Radang akut & kronik arteri kecil-sedang yg

segmental dan trombosis terutama a. radialis dan

tibialis, kemudian menyebar ke vena dan saraf
pada ekstremitas

Pathogenesis :

Toksisitas secara langsung pada sel endotel

akibat komponen dari rokok tembakau atau reaksi
hipersensitif terhadap terhadap agen yg sama

Thromboangiitis obliterans (Buerger disease). The lumen is occluded by a thrombus

containing abscesses (arrow), and the vessel wall is infiltrated with leukocytes.

Raynaund phenomenon

Vasokonstriksi yg berlebihan arteri dan arteriola jari.

Warna pucat atau sianosis pada jari tangan & kaki.
Perubahan warna dari merah (vasodilatasi), putih

(vasokonstriksi), biru (sianosis) jari

Primer (raynaund dis.): respon vasomotor sentral/lokal

yg berlebihan thd dingin atau stress emosional

Sekunder : karena kelainan arteri spt SLE,

scleroderma

Raynaud's phenomenon. A, Sharply demarcated pallor of the distal fingers resulting from
the closure of digital arteries. B, Cyanosis of the fingertips.