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Thrombotic microangiopathy


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Thrombotic microangiopathy (TMA) is a pathology that results in thrombosis in capillaries and arterioles, due to an endothelial injury.

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Thrombotic microangiopathy

  1. 1. THROMBOTIC MICROANGIOPATHY Mr.Jagdish sambad M.Sc. Nursing in Nephrology IKDRC College of Nursing AHMEDABAD
  2. 2.  Pathologic term for a condition characterized by microvascular changes including thrombosis in association with laboratory abnormalities of microangiopathic hemolytic anemia (MAHA) and thrombocytopenia. Definition
  3. 3. Classification  Classic HUS  Atypical HUS  Familial  Sporadic (idiopathic)  Streptococcus pneumoniae associated  Cobalamin C (cblC) disorder  Secondary forms  Infections  Autoimmune disorders  Drugs  Pregnancy/postpartum  HELLP syndrome  Other  TTP  Congenital  Idiopathic  Secondary forms  Infections  Autoimmune disorders  Drugs  Pregnancy/postpartum  HELLP syndrome  Other
  4. 4.  Other TMAs  Glomerulopathies  Malignant hypertension  Malignancies  Solid organ transplantation  Scleroderma renal crisis  Radiation nephropathy  HSCT
  5. 5. Classification of HUS and TTP
  6. 6. Thrombotic microangiopathies other than classic and aHUS and TTP  Infections  Systemic infections, human immunodeficiency virus infection, H1N1 influenza, Salmonella typhi, others  Autoimmune diseases  SLE, APS, others  Drugs  Quinine, ticlopidine, clopidogrel, anti-VEGF agents, oral contraceptives, mitomycin C, interferon, gemcitabine, CNIs, sirolimus, and others  Pregnancy/postpartum  HELPP syndrome  Glomerulopathies  Malignant hypertension  Malignancies  Solid organ transplantation  Scleroderma renal crisis  Radiation nephropathy  HSCT
  8. 8. Epidemiology  Young children  O157:H7 serotype of Shiga toxin-producing E. coli (STEC) infection in United States  Shiga toxin-producing Shigella dysenteriae serotype 1 in asia and africa  Annual incidence of classic HUS is estimated to be 21 per 1 million with a peak incidence in children under the age of 5 years
  9. 9. Transmission  Cattle are considered to be the most important source of human infections  Human infection typically occurs through acquisition of the bacteria via consumption of contaminated food, water, or by person-to-person transmission
  10. 10. Clinical presentation  Begins with watery diarrhea and may progress rapidly to bloody diarrhea with hemorrhagic colitis.  Second phase occurs abruptly within 3 to 4 days of the onset of gastrointestinal symptoms,characterized by various combinations of acute renal failure, proteinuria, hematuria, anemia, bleeding abnormalities, central nervous system disorders and cardiovascular changes  The prognosis is relatively good with most patients fully recovering
  11. 11. Renal manifestations  Oliguria or anuria, hematuria, hemoglobinuria, proteinuria, various types of casts in the urine  Hyperkalemia  Elevated blood urea nitrogen (BUN) and serum creatinine level
  12. 12. Laboratory findings  Helmet cells, burr cells, and fragmented cells (schistocytes) in the peripheral blood  Reticulocytes are increased.  The Coombs test is almost invariably negative.  Leukocytosis is common in the early stages.  Platelets are decreased to varying degrees  Serum lactic dehydrogenase level and concomitant reduction in the serum haptoglobin  Normal PT,APTT
  13. 13. MAHA Shistocytes Elevated LDH & Bilirubin Mechanical fragmentation of erythrocytes during flow through partially occluded, high shear small vessels 1
  14. 14.  Nonenteropathic or diarrhea-negative  Affects both children and adults  5% to 12% of all cases of HUS  Majority of cases are sporadic, and approximately 20% to 30% are familial  Genetic or acquired abnormalities of the complement regulatory proteins have been identified as the most common etiology in the aHUS group Atypical HUS
  15. 15.  Develop without prior diarrhea and/or hemorrhagic colitis.  The onset is usually sudden with general distress, fatigue, vomiting, and drowsiness.  In most patients, the diagnostic triad of MAHA, thrombocytopenia, and renal impairment are present. Atypical HUS
  16. 16.  The prognosis of aHUS is poor  The mortality rate is 10% to 15% during the acute phase  50% of patients develop end-stage renal disease
  17. 17. TTP - First described Dr. Eli Moschcowitz Arch Intern Med. 1925;36:89. 3
  18. 18. “Classic Signs”  Fever  Thrombocytopenia  Neurological abnormalities  Microangiopathic hemolytic anemia  Renal dysfunction TTP
  19. 19.  Rare disease with a reported incidence of 6 cases per million  Peak incidence in 3rd decade of life  Higher among females,African Americans and obese patients  The clinical features of TTP are similar to those of aHUS, and in most instances TTP
  20. 20.  The clinical diagnosis of TTP requires exclusion of other etiologies, such as systemic infection or another cause of TMA.  Since renal involvement in TTP is typically mild, the renal prognosis is good TTP
  21. 21. Relationship Between Hemolytic-Uremic Syndrome and Thrombotic Thrombocytopenic Purpura TTP  occurs among adults  affects the central nervous system more commonly  exhibits less frequent and less severe involvement of the kidney  involves multiple organs and has a poorer prognosis
  23. 23. One underlying fact Endothelial damage [stx,Complement,neuraminidase,drugs] Exposure of subendoth.surface with Platelet activation and aggregation Thrombi and cellular proliferation in glomeruli and arterioles. Red blood cell hemolysis is caused by mechanical disruption in traversing fibrin meshwork of microcirculation
  24. 24. CLASSIC HUS
  25. 25. ATYPICAL HUS
  26. 26. Streptococcus pneumoniae- Associated HUS  Neuraminidase producing organisms  Expose the usually hidden T-crypt antigen  Preformed circulating IgM antibodies to this antigen, the antigen-antibody reaction followed by complement activation through the classical pathway damages endothelial, red-cell, and platelet surfaces and leads to intravascular thrombosis, hemolysis, and thrombocytopenia
  27. 27. Platelets vWF ADAMTS 13 What is ADAMTS 13, and What is its role? 4
  28. 28. Absence of or Abs to ADAMTS 13 → Persistent vWF large multimers → Platelets microthrombi What is ADAMTS 13, and What is its role? Platelets vWF ADAMTS 13 4
  29. 29. TTP
  31. 31. Systemic infections  Brucellosis, streptococcal infection with acute glomerulonephritis, angioinvasive fungal infections, CMV, HIV, ehrlichiosis, and Rocky Mountain spotted fever, may cause microvascular injury
  32. 32. TMA,Drugs  aHUS caused by drugs  Direct endothelial injury or immune mediated  Chemotherapeutic drugs  Anti-VEGF  CNIs  Antiplatelet drugs  quinine
  33. 33. Antiphospholipid antibodies  The most common renal manifestations of APS are those of microvascular thrombotic lesions, that is, TMA.  Acute TMA may present with rapidly progressive renal failure, proteinuria, sometimes in the nephrotic range, and severe hypertension, often in the malignant range, MAHA and thrombocytopenia can also be seen.  Chronic TMA, the clinical presentation is more subtle
  34. 34. Hematopoietic stem cell transplant  Multifactorial  Radiation  Cyclosporine and tacrolimus  Cmv,fungal and H.pylori  GVHD  HLA mismatched transplants  No ADAMTS13 abnormaility
  35. 35. Postpartum HUS  Symptoms manifest postpartum within 24 hrs to several weeks  Etiology-  Genetic abnormailities in complement system  Increased susceptibility during postpartum
  36. 36. Systemic sclerosis  Endothelial damage of the arteries and arterioles in the kidney.  Undue permeability of the endothelial barrier  Endothelial damage may also initiate a chain of events leading to coagulation and release of factors
  37. 37. Cancer associated TMA  Stomach, breast and prostate cancers  Insidious onset  Pathophysiology can be due to either:  –tumor microemboli leading to microvascular occlusion  –cytokines (ie.TNFα) leading to endothelial injury  –acquired ADAMTS-13 deficiency (paraneoplastic syndrome)  Poor prognosis
  38. 38. Intraluminal platelet thrombosis Thrombocytopenia Consumption of platelets TTP Shiga toxin HUS Atypical HUS ADAMTS 13 Toxin binds endothelium Alternative Complement What is the mechanism of TMA in TTP-HUS? 1
  40. 40. Gross Appearance  Renal cortical necrosis  Calcification  Petechial hemorrhages are seen in an enlarged, swollen kidney  In chronic phase,kidney are small with granular cortical surface
  41. 41. Light Microscopy
  42. 42.  The glomerulus is slightly hypocellular, and most of the glomerular capillary lumina are closed due to thickening of the capillary walls. Red blood cells and fragmented red blood cells are seen in the mesangial areas.
  43. 43.  “Bloodless” glomerulus. The glomerular capillary walls are thickened, and the mesangial areas blend with the capillaries.
  44. 44.  The mesangial areas of the glomerulus have fibrillary appearance. Focal reduplication of the glomerular capillary basement membranes is also seen. A few intracapillary polymorphonuclear leukocytes are present.
  45. 45.  Most of the glomerular capillary lumina are occluded by homogenous eosinophilic thrombi.
  46. 46.  Thrombotic microangiopathy, associated with cyclosporine administration. Some of the glomerular capillary lumina are occluded by thrombi
  47. 47.  Some of the glomerular capillary tufts are permeated by eosinophilic acellular material. This change is often described as fibrinoid necrosis. Intraluminal thrombi are also present.
  48. 48. Thrombotic microangiopathy, secondary to abruptio placentae Thrombotic microangiopathy in a patient with primary antiphospholipid antibody syndrome Some of the glomerular capillary lumina are occluded by fibrin thrombi; the rest of the capillaries are congested The dilated vascular pole is occluded by a thrombus
  49. 49. Ectatic glomerular capillary lumina are present as a result of mesangiolysis. Focal reduplication of the glomerular capillary basement membranes is also seen Thrombotic microangiopathy, associated with mitomycin administration Thrombotic microangiopathy, postpartum The dilated infundibulum is occluded by homogenous eosinophilic material (intraluminal thrombus). Extensive reduplication of the glomerular capillary basement membranes
  50. 50. Chronic or advanced stage of TMA  extensive reduplication of the glomerular capillary basement membranes.
  51. 51. Arteriolar fibrinoid necrosis The infundibulum (i.e., vascular pole) is occluded by a large thrombus. The glomerular capillary walls are thickened Arteriolar and arterial changes are more common in patients with aHUS and TTP
  52. 52.  The small interlobular artery shows the edematous intima containing few myointimal cells (“mucoid intimal hyperplasia”)
  53. 53. The interlobular artery shows luminal thrombus with nuclear debris in the arterial wall. The glomerulus exhibits ischemic features with thickening and wrinkling of the glomerular capillary basement membranes. Prominent circumferential intimal cellular proliferation in a small interlobular
  54. 54. Tubules and interstitium  Hyaline casts and red blood cells.  Acute tubular necrosis as is seen with ischemia may be present. Iron pigment and hyaline droplets  In later stages, tubular atrophy may be seen  Interstitium may be edematous or fibrous, and in some cases, it contains mild mononuclear cell infiltration.  Large numbers of red blood cells are present in the interstitium in areas of cortical necrosis.
  55. 55. Immunofluorescence Microscopy The glomerular capillary walls and lumina (A) and the arterial wall (B) show strong fibrinogen positivity
  56. 56. Electron Microscopy The subendothelial zone is lucent and contains fluffy material
  57. 57. Fibrin and platelets in the capillary loop are clearly recognizable. The foot processes of the visceral epithelial cells reveal moderate effacement Reduplication of the glomerular capillary basement membrane with cellular interposition.Severe thickening of the glomerular capillary basement membrane
  58. 58. The arteriolar lumen is obliterated, and the subintima is widened by a lucent zone containing electron-dense strands and granules
  59. 59. Outcome and Prognostic Features  Acute renal failure manifests in up to 70% of patients with classic HUS, most patients recover  Pediatric patients with aHUS have a worse prognosis and renal outcome than those with classic HUS  A number of clinical-laboratory features such as the severity of gastrointestinal tract symptoms , the longer duration of dialysis , the duration of anuria, hypertension, initial peripheral leukocytosis, and neurologic involvement during the acute phase have been proposed as predictors for poor long-term renal outcome in pediatric patients with HUS
  60. 60. Treatment  Plasma exchange  Corticosteroids  Rituximab  Eculizumab  Combined liver-kidney transplants
  61. 61. THANK YOU