Fußzeile (Titel der Präsentation) 1. Thrombotic Microangiopathy: The German Experience 4. Conflictof interest: none
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1 Thrombotic Microangiopathy: The German Experience 3 Nephropathology Section, Institute of Pathology, Hamburg, Germany Agenda 1. Difficulties in the diagnosis TMA 2. Previous efforts to reach consensus (first round ) 3. Intermediate results Thrombotic Microangiopathy: The German Experience 4. Second round ( ) 5. Application: is Bevacizumab glomerulopathy a TMA? Thorsten Wiech, Maastricht 2018 Thrombotic Microangiopathy: The German Experience 2 Thrombotic Microangiopathy: The German Experience 4 Conflictof interest: none 1924 Moschcowitz: description of TTP: multiple thrombi in arterioles and capillaries 1955 Gasser: description of HUS: hemolytic anemia, thrombocytopenia and renal failure, corticalnecrosis 1958 Habib et al. proposed the term thrombotic microangiopathy for the vascular lesions of both HUS and TTP (Symmers) Microscopic features of scleroderma renal crisis, malignant hypertension and others can be similar to HUS and TTP 1980 Thoenes and John proposed the term endotheliotropic nephroangiopathy for TMA/TTP, HUS and malignantnephrosclerosis Fußzeile (Titel der Präsentation) 1
2 Thrombotic Microangiopathy: The German Experience 5 Thrombotic Microangiopathy: The German Experience 7 Is Thrombotic MicroAngiopathy a pathological diagnosis? Is it a clinical diagnosis? Coombs-negative hemolysis, fragmentocytes / schistocytes, increased LDH Commen final path: damageof the endothelial cell MAHA: MicroAngiopathic Hemolytic Anemia Pathological lesions: endothelial cell damage and reaction Clinical definition Pathological definition TMA? MAHA? ctma? TMA? endotheliotropic microangiopathy? ptma? TMA? cptma? Keir, Coward, 2011 Pediatr Nephrol Thrombotic Microangiopathy: The German Experience 6 Autor (Vorname Nachname) Fußzeile (Titel der Präsentation) 8 thrombotic : with blood clots / fibrin precipitates But: diagnosis of TMA possible also without fresh thrombi (sensitivity < 100%) TMA TMA? TMA? And: fresh thrombi are not always a positive proof of TMA (specificity < 100%) CD 61 CD61 Fußzeile (Titel der Präsentation) 2
3 Thrombotic Microangiopathy: The German Experience 9 Thrombotic Microangiopathy: The German Experience 11 Morphology of TMA = tissue reaction to endothelial damage fresh old The older the lesion, the more differential diagnoses Thrombi in the glomerular capillaries Fibrin precipitates and/or aggregates of thrombocytes in one or more capillary lumen without space to the capillary wall, at least half of the luminal area without evidence for another cause (e.g. cholesterol / bone marrow embolism). TMA TMA? Hypertension? Chronic rejection? TMA? Hypertension? Chronic rejection? Status after Vasculitis? CD61 CD34 Thrombotic Microangiopathy: The German Experience 10 Thrombotic Microangiopathy: The German Experience 12 Criteria Glomeruli Arteries/Arterioles Tubulointerstitium Thrombi (fibrin/thrombocytes) Erythrocytes/fragmentocytes Ischemic necrosis Erythrocytes/fragmentocytes Thrombi (fibrin/thrombocytes) Special tubular atrophy Thrombocytes Intramural fibrin Fresh Mesangiolysis Subintimal edema Subendothelial edema Onion skin Loss of endothelium Foam cells Double contours Intima sclerosis Endotheliosis Loss of endothelium Older mesangiolysis Myointimal proliferation Bloodless glomeruli Endothelial swelling Glomerular collapse Obliteration Solidification Transmural hyalinosis Erythrocyte stasis Calcification Hyaline thrombi Granulocytes Definition Fragmentocytes (arterioles) At least two erythrocytes or fragments of erythrocytes outside the vessel lumen: in the subendothelial space / in the intima or in the vessel wall Fußzeile (Titel der Präsentation) 3
4 Autor (Vorname Nachname) Fußzeile (Titel der Präsentation) 13 Thrombotic Microangiopathy: The German Experience 15 Double contours or multilayering of the GBM... Trying to find consensus criteria... Double contours or multilayering of the peripheral glomerular basement membrane in at least two capillaries (without evidence for another cause, such as collapse or MPGN) First round: 2015: 6 pathologists Light microscopic criteria 2016: completed criteria : refined defintions 12 TMA cases, 4 pathologists Problems: Too clear TMA cases, not anonymously Not enough cases No EM, no IHC Second round ( ): Talked to statistician before 12 renal pathologists from different countries At least 30 cases Anonymously Include EM and IHC Include more uncertain cases from different centers Thrombotic Microangiopathy: The German Experience 14 Thrombotic Microangiopathy: The German Experience 16 Endothelial swelling Criteria Scoring of the single lesions: 0 = not relevant for the diagnosistma (does not represent TMA lesion) 1 = weakly indicative for TMA (likely is not caused by TMA, has too many differential diagnoses, but TMA cannot be ruled out) 2 = moderately indicativefor TMA (couldwell be due to TMA, but other causes cannot be ruled out) 3 = strongly indicative for TMA (very likely is TMA) Fibrin thrombus Double contours Mesangiolysis TMA Intuition TMA! Fußzeile (Titel der Präsentation) 4
5 Thrombotic Microangiopathy: The German Experience 17 Thrombotic Microangiopathy: The German Experience 19 Mean score per case (0-3) Interobserver variability Summary Pathological term TMA needs to be defined Best way of calculation / combination of the single lesions Different causes can lead to TMA lesions, common final path = damage of the endothelial cell Pathological criteria = endothelial cell damage and reactions Find consensus criteria by opinionaires and virtual microscopy Single lesions present or not Interobserver variability Aim: better concordance between pathologists TMA or suspicious for TMA, better communication with clinicians, better standardization for studies Establish and recheck a model by intuitive diagnosis and single criteria Aim: better concordance between pathologists, better communication with the nephrologists, better standardization for studies Application of criteria: Bevacizumab glomerulopathy is not a typical TMA Bevacizumab: anti-vegf-antibody for cancer treatment TMA Bevacizumab Cryoglobulinemia Fibrin thrombi Wall adherent Dilatation No hypercellularity Hyaline pseudothrombi Wall adherent Dilatation No hypercellularity Hyaline pseudothrombi Not wall adherent No dilatation Hypercellularity Fußzeile (Titel der Präsentation) 5
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