TMA types and pathology

1. THROMBOTIC
MICROANGIOPATHIES

2. TMA is a pathological term used to describe diseases/conditions characterized by
occlusive microvascular thrombosis, and their end results on the organ system,.
First described in 1952 by Symmers
Endothelial
injury
Thrombus
formation
End organ
damage

3. The thrombotic microangiopathies (TMAs) are classified together due to
their overlapping clinical and morphologic findings.
Essential
of
Diagnosi
Thrombocytopenia
Thrombosis
Renal Failure
Vascular wall
thickening and/or
necrosis
Microangiopathic
hemolytic anemia

5. Keir L, Coward RJ. Advances in our understanding of the pathogenesis of glomerular
thrombotic microangiopathy. Pediatr Nephrol. 2011 Apr;26(4):523-33

8. The role of kidney biopsy in TMA
• Will provide the diagnosis of TMA – The diagnosis is frequently made by
renal pathologists; the clinical presentation may not be typical (hence the
name atypical HUS)
• Will tell whether the disease is acute active or chronic
• Will provide some therapeutic guidelines – Cases with advanced chronic
injury may not respond to treatment
• Does not differentiate between different forms of TMA – There are some
hints though, e.g. in malignant HTN there is usually less glomerular
involvement

9. RENAL PATHOLOGY IN TMA
ACUTE STAGE

10. Glomeruli
• Bloodless appearance
• Apparent thickening of capillary wall due to subendothelial expansion
• Mesangiolysis
• Endothelial swelling
• Thrombi in glomerular capillaries or hilum
• Fibrinoid necrosis may be present
• Rare crescents seen in occasional cases
• Fragmented red blood cells (RBCs) entrapped in thrombi, subendothelium, and mesangium
• In presence of arteriolar changes, downstream glomeruli demonstrate ischemic collapse of capillary tufts
• Segmental sclerosis with collapsing features may be observed
Tubulointerstitium
• Acute tubular injury characterized by simplified epithelium, nuclear reactive atypia
• Interstitial edema
• Cortical necrosis in severe cases
Blood vessels
• Arterioles near vascular pole affected frequently
• Endothelial swelling and luminal occlusion
• Intimal mucoid edema with entrapped schistocytes
• Thrombi
• Fibrinoid necrosis may be present
• Immunohistochemical staining using CD61 may support TMA diagnosis

14. RBCs and fibrin fill up capillary loops in glomerulus in thrombotic microangiopathy
(Jones’ silver stain) –Agnes Fogo

15. Fibrin thrombi extending from glomerulus into arteriole in thrombotic microangiopathy
(Jones’ silver stain) –Agnes Fogo

20. Chronic Thrombotic Microangiopathy
Changes may be seen within days of acute onset of TMA
• Glomeruli
• GBM duplication and double contours
• Mesangial expansion with features of mesangiolysis
• Variable focal segmental and global glomerulosclerosis
• Tubulointerstitium
• Tubular atrophy and interstitial fibrosis
• Arterioles and small arteries
• Intimal fibrosis with narrowed lumina
• Concentric lamination of intimal fibrosis causes onion-skin appearance
• Recanalized thrombi may be identified

27. Immunofluorescence Microscopy
• Thrombi in glomeruli and blood vessels stain for fibrinogen (and CD61)
• Nonspecific entrapment of C3, C1q and IgM in glomeruli
• No immune complexes unless associated with connective tissue disorder, such as SLE
Electron Microscopy
• Acute TMA
• Endothelial swelling and loss of fenestrations
• Expansion of subendothelial space by electron-lucent material
• Entrapped schistocytes and fibrin tactoids in subendothelium
• Podocyte foot process effacement common
• Thrombi show mixture of platelets, fibrin, and erythrocytes
• Chronic TMA
• Increased matrix in mesangium and subendothelium
• Depolymerized fibrin may be identified
• Duplication of GBMs
• Mesangial cell interposition
• Mucinous, onion skin-type obliterating endarteritis

30. Fibrin tactoids in subendothelial area by EM in thrombotic microangiopathy. –Agnes Fogo

31. Duplication of the GBM (arrowheads) is a chronic feature of TMA

32. Immunofluorescence microscopy demonstrates strong staining for fibrinogen in this small artery, which is occluded by a thrombus.
Other immunoglobulin and complement components can also be present in injured vessels, but the staining intensity is typically
much lower.