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SIAPEC - IAP ROMA, 26 -30 november 2013
Il ruolo del Patologo nella diagnostica e nella ricerca in tema di Patologia Vascolare - Microvessels in Large Vessel Pathology -
Allard C van der Wal, MD. Afdeling Pathologie M2-129 AMC Amsterdam
[email protected]
Academisch Medisch Centrum Universiteit van Amsterdam
Microvascular pathology Widespread in biopsies of nearly all organs
…. and contributes significantly also to the diseases of large arteries
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Microvascular pathology Widespread in biopsies of nearly all organs …. and contributes significantly also to the diseases of large arteries - coronary atherosclerosis
- aortic aneurysms - vascular tumors & malformations
Coronary atherosclerosis Normal coronary artery
Atherosclerotic coronary artery
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PLAQUE ANGIOGENESIS - Mechanism
1. Intimal plaque thickening (plaque growth)
reduced oxygen transmobility * exceeds maximal distance of oxygen diffusion (100-250mm)
2. Plaque inflammation
oxygen consumption * foam cell macrophages
Tissue Hypoxia hypoxia responsive gene expression (VEGF, GLUT1/3, Hexokinases
Hypoxia inducible transcription factors, HIF1a HIF2a Angiogenesis
ACUTE CORONARY PLAQUE COMPLICATIONS
Plaque rupture / erosion
Occlusive thrombus
Rupture of microvessels
Intraplaque hemorrhage
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H&E
CD31
Intraplaque hemorrhage Mechanism: rupture / leakage of microvessels
Implications: rapid plaque expansion of plaque volume
Von Willebrand factor
- Kolodgie FD et al. N Engl J Med 2003;349: 2316-25
Microvessels and coronary plaque hemorrhage •
Inflamed (vulnerable plaques) have significantly more micro-vessels than fibrous (stable) plaques » Onno de De Boer et al. Cardiovascular Research 1999;
•
Plaque hemorrhages occur more frequently and are much larger in coronary arteries of patients treated with oral anticoagulant therapy (Total of 990 plaques) » Xioafei Li et al, Submitted
•
52% of 115 plaques retrieved from aged patients with extensive coronary atherosclerosis had signs of plaque hemorrhages (fresh, ongoing or organized) » Xiaofei Li et al, Histopathology 2012;
•
A Similar pattern of plaque hemorrhages and microvessels can be noticed also in the lesions of Chronic Transplant Vasculopathy » Chiara Castellani et al, Am J Transplant 2013; in press
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CORONARY PLAQUE VULNERABILITY & INSTABILITY
Anti-vWF
A Clue to pathology: - Microvascular angiogenesis - Dedifferentiation towards dilated “leaky” vessels
II. Immune responses in Aortic Aortic Aneurysm
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Atherosclerotic Aortic Dilatation - 3 levels of inflammatory pathology Intimal ulceration and thrombosis
Medial thinning and destruction
Advential nodular infiltration
• Unlike the intimal plaque related inflammatory process, Adventitial inflammation shows: •Diffuse infiltrates and additional Nodular architecture •B-cells and plasma cells at different stages of maturation (CD20, CD45R0, CD79a, CD138) •Follicular dendritic cells (CD21+) antigen presentation •Apoptotic foci (caspase 3, Bcl2) (selection of B-cells) Heca 452
•Angiogenesis, lymfangiogenesis and the formation of High Endothelial Venules (Heca 452+)
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Adventitial infitrates of atherosclerotic arteries • Follicular differentation, de novo formation of HEV’s • Homing and selection of B lymfocytes • Production of IGM, IgG Antibodies • Has similarities with mucosal associated lymfoid tissues (MALT)
• Vascular Associated Lymfoid Tissue (VALT)
Aortic aneurysms chronic (auto immune) aortitis ( n=39) versus advanced atherosclerosis (n=12) Presence and extent of follicular adventitial infiltrates resembling MALT 100 90 80
% of patients
70 60 50 40 30 20 10 0 Aortitis total
necrotising aortitis
fibrous aortitis
atherosclerosis
controls
Dingemans W et al. Virchows Archives 2009;455;239
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Adventitial Inflammation in Aortic Aneurysms
- atherosclerosis - chronic aortitis
A Clue to pathology - Angiogenesis - Lymfangiogenesis - Diferentiation towards high endothelial venules (HEV’’s)
III. Angiogenesis in Angioma and Malformations
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12 years old VASCULAR MALFORMATIONS (VM)
- Congenital - Slowly progressive growth - Large mature (dysplastic ) vessels
- 29 out of 107 symptomatic patients (30%)
40 years old
features of intralesional proliferations of microvessels
-Nearly all (94%) of the Arteriovenous type (AVM)
VASCULAR MALFORMATIONS OF SKIN & SOFT TISSUE
Symptomatic lesions
CLINICAL CLASSIFICATION
and angiogenesis High (fast) Flow
Low (slow) Flow
% AVM
100
- Nearly all are Arteriovenous lesions of the ‘high flow’ type
0 1 2 3
50
- sudden growth of lesions relates to microvascular proliferative responses
- has features of proliferatieve angiomas (in contradiction with current classification of vascular lesions)
0 High flow
Low flow
Meijer-Jorna et al , J Clin Pathol 2007 / J Am Acad Dermatol 2013
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International Society for the Study of Vascular Anomalies
(ISSVA) 1996
Vascular tumors
Vascular malformations
Infantile hemangioma Congentile hemangiomas (RICH and NICH) Tufted angioma Kaposiform hemangioendothelioma Hemangiopericytoma Pyogenic granuloma Spindle cell hemangioendothelioma
Simple
Combined
Capillary Lymphatic Venous Arterial
AVF, AVM CVM, CLVM LVM, CAVM CLAVM
+
_
Sudden Growth in ‘’high flow” types of AVM
Clue to pathology: - Angiogenesis - Massive proliferation of immature capillary microvessels
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VEGF ANG2 VEGF
ANG2 ANG1
sprouting ANG2
apoptosis
Thanks
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plaque angiogenesis appears an adaptive process to counteract hypoxia, and can be disproportionately increased by the effects of plaque inflammation
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microvessels
Is there a relationship between flow characteristics and the occurrence of microvascular proliferation?
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