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Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad

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Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad

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Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad

  1. 1. TTP/HUS r Questions & Answers Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria drgawad@gmail.com ESNT Outreach Program, Sohag, December 4-7, 2014
  2. 2. To download the lecture with full animations please contact me on drgawad@gmail.com
  3. 3. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 1
  4. 4. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 1
  5. 5. What is meant by Thrombotic Microangiopathy (TMA)? Intraluminal platelet thrombosis Thrombocytopenia Microangiopathic hemolytic anemia Consumption of platelets Hemolysis, Anemia, ↑LDH & Bilirubin 1
  6. 6. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 2
  7. 7. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 2
  8. 8. What are the causes of ?TMA HIV, TTP/HUS 2
  9. 9. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 2
  10. 10. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 2
  11. 11. What is the mechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Thrombocytopenia Microangiopathic hemolytic anemia Consumption of platelets Hemolysis, Anemia, ↑LDH & Bilirubin 2
  12. 12. What is the mechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS Neuraminidase HUS Atypical HUS 3
  13. 13. What is the mechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS Neuraminidase HUS Atypical HUS 3
  14. 14. What is vWF role in ?body Flora Peyvandi et al. Blood Transfus 2011; 9 Suppl 2:s3-s8- . Romijn RAP et al. J Biol Chem 2001; 276: 9985-91- ·Leo T. Kroonen et al. Orthopedics. March 2008 - Volume 31- 3
  15. 15. What is vWF role in ?body vWF activation = Platelets Aggregation & Adhesion Flora Peyvandi et al. Blood Transfus 2011; 9 Suppl 2:s3-s8- . Romijn RAP et al. J Biol Chem 2001; 276: 9985-91- ·Leo T. Kroonen et al. Orthopedics. March 2008 - Volume 31- 3
  16. 16. TTP - Classification - H-M Tsai. Kidney International (2006) 70, 16–23. -Tsai HM. Annu Rev Med 2006; 57: 419–436. - Allford SL et al. Br J Haematol. 2003;120:556-573. 5
  17. 17. What is the mechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS 6
  18. 18. What is the mechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS 6
  19. 19. Shiga Toxin Associated HUS E. coli (STEC) S. dysenteriae watery or most often bloody diarrhea E.Coli: Mostly the serotype O157:H7, but also other serotypes, such as O111:H8, O103:H2, O123, O26, O145, and the O104:H4 strain of the recent German outbreak Mead PS, Griffin PM. Lancet.1998;352:1207-1212. Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058. 6
  20. 20. Shiga Toxin Associated HUS E. coli (STEC) S. dysenteriae watery or most often bloody diarrhea Mead PS, Griffin PM. Lancet.1998;352:1207-1212. Ruggenenti P, Remuzzi G.Lancet. 2011;378:1057-1058. 6
  21. 21. Shiga Toxin Associated HUS E. coli (STEC) S. dysenteriae watery or most often bloody diarrhea Morigi M et al. Blood. 2001;98:1828-1835. Morigi M et al. J Immunol. 2011;187:172-180. 7
  22. 22. Shiga Toxin Associated HUS E. coli (STEC) S. dysenteriae watery or most often bloody diarrhea Complement activation by alternative pathway: High plasma levels of complement activation products Bb and C5b-9 were measured in children with STEC-HUS Morigi M et al. Blood. 2001;98:1828-1835. Morigi M et al. J Immunol. 2011;187:172-180. 7
  23. 23. What is the mechanism of Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS Toxin binds endothelium TMA in TTP-HUS? 8
  24. 24. What is the mechanism of Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS Toxin binds endothelium TMA in TTP-HUS? 8
  25. 25. Neuraminidase Associated HUS In infants and children. Complicate pneumonia, or less frequently, meningitis caused by S. pneumoniae erythrocytes, platelets, glomerular cells Brandt J, Wong C, Mihm S, et al. Pediatrics. 2002;110:371-376. Thomsen-Friedenreich antigen 8
  26. 26. Neuraminidase Associated HUS In infants and children. Complicate pneumonia, or less frequently, meningitis caused by S. pneumoniae erythrocytes, platelets, glomerular cells Thomsen-Friedenreich antigen Polyagglutination Brandt J, Wong C, Mihm S, et al. Pediatrics. 2002;110:371-376. 8
  27. 27. Neuraminidase Associated HUS In infants and children. Complicate pneumonia, or less frequently, meningitis caused by S. pneumoniae erythrocytes, platelets, glomerular cells Thomsen-Friedenreich antigen Polyagglutination Brandt J, Wong C, Mihm S, et al. Pediatrics. 2002;110:371-376. 8 Coomb’s +ve
  28. 28. What is the mechanism of Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS Toxin binds endothelium TMA in TTP-HUS? 8
  29. 29. What is the mechanism of Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS Toxin binds endothelium TMA in TTP-HUS? 8
  30. 30. Atypical HUS Low serum C3 levels in aHUS with normal C4 indicate selective .alternative pathway activation Noris M, Ruggenenti P, Perna A, et al. J Am Soc Nephrol. 1999;10:281-293. 9
  31. 31. Atypical HUS Caprioli J et al. Blood. 2006;108:1267-1279. Manuelian T, et al. J Clin Invest. 2003;111:1181-1190. 9
  32. 32. Atypical HUS 9
  33. 33. Atypical HUS 10
  34. 34. Atypical HUS Acquired defects of CFH function are also seen in the form of inhibitory antibodies, reported in 5% to 10% of aHUS patients. Dragon-Durey MA, Loirat C, Cloarec S, et al. J Am Soc Nephrol. 2005;16:555-563. 10
  35. 35. Atypical HUS 10
  36. 36. What is the mechanism of Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS Toxin binds endothelium Alternative Complement TMA in TTP-HUS? 10
  37. 37. What is the mechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Thrombocytopenia Microangiopathic hemolytic anemia Consumption of platelets Hemolysis, Anemia, ↑LDH & Bilirubin 11
  38. 38. TTP – MAHA 11
  39. 39. To download the lecture with full animations please contact me on drgawad@gmail.com
  40. 40. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 12
  41. 41. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 12
  42. 42. Marie Scully et al. British Journal of Haematology, 2012, 158, 323– 335. HIV, DD of thrombocytopenia & MAHA Systematic Approach of Diagnosis 12
  43. 43. Systematic Approach Marie Scully et al. British Journal of Haematology, 2012, 158, 323– 335. of Diagnosis Step 1 – Exclude Drugs 12
  44. 44. Systematic Approach Piero Ruggenenti, Comprehensive Clinical Nephrology. 4th edition, chapter 28, p353 of Diagnosis Step 1 – Exclude Drugs 12
  45. 45. Systematic Approach of Diagnosis Step 1 – Exclude Drugs Step 1 – Exclude Drugs 12
  46. 46. Systematic Approach of Diagnosis - Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335. - Patton JF et al. Am J Hematol. 1994;47:94-99. Step 2 – Autoimmune Hemolysis 13
  47. 47. Systematic Approach of Diagnosis - Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335. - Patton JF et al. Am J Hematol. 1994;47:94-99. Step 2 – Autoimmune Hemolysis 13
  48. 48. Systematic Approach of Diagnosis - Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335. - Patton JF et al. Am J Hematol. 1994;47:94-99. Step 2 – Autoimmune Hemolysis Step 3 13
  49. 49. Systematic Approach of Diagnosis Step 3 – Coagulation Profile Step 4 – Exclude other causes 14
  50. 50. Systematic Approach of Diagnosis Step 4 – Exclude other causes DD Suggestive Criteria Malignant Hypertension • Patient will have severe HTN: for example, systolic BP >200 mmHg, diastolic BP >130 mmHg. • It is extremely unlikely that a patient with TTP will present with severe HTN. • Microangiopathic haemolysis in patients with malignant HTN clears and thrombocytopenia resolves with BP management. Pre-eclampsia • New BP elevation and proteinuria after 20 weeks of gestation in a pregnant woman. • Although pregnancy is a risk factor for TTP and proteinuria can be present, patients with TTP do not generally have raised BP. 15
  51. 51. Systematic Approach of Diagnosis Step 4 – Exclude other causes DD Suggestive Criteria Sepsis • Sepsis patients have hypotension • More pronounced fever • Raised white count with left shift. • Peripheral smear: vacuoles in the cytoplasm of neutrophils (highly specific for bacteraemia) • Blood cultures might be positive. Pregnancy Must be excluded. Autoimmune Disease ANA, RF, antiDNA, ACLA, lupus anticoagulant 16
  52. 52. Systematic Approach of Diagnosis Step 4 – Exclude other causes HIV, 17
  53. 53. Systematic Approach of Diagnosis Step 4 – Exclude other causes 17
  54. 54. Systematic Approach of Diagnosis Step 4 – Exclude other causes • TTP has been reported in association with acute pancreatitis. • Sometimes a number of days after resolution of pancreatitis. • All patients were successfully treated with PEX and corticosteroids (McDonald et al, 2009). An association between thrombocytopenia and thyrotoxicosis has been reported 17
  55. 55. Systematic Approach of Diagnosis Atypical HUS TTP Step 5 – TTP vs HUS Shiga toxin- HUS Neuraminidase -HUS 18
  56. 56. Systematic Approach of Diagnosis Step 5 – TTP vs HUS Shiga toxin- HUS - Less than 2 years old - Respiratory distress, neurologic involvement, and coma. Neuraminidase -HUS - Occurs primarily in children, (except in epidemics with any age) -Watery or bloody diarrhoea. - Stool Culture: detection of E. coli O157:H7 and other STEC and their products in stool cultures (sorbitol-containing MacConkey agar - SMAC) Mead PS, Griffin PM. Lancet. 1998;352:1207-1212. 18
  57. 57. Systematic Approach of Diagnosis Step 5 – TTP vs HUS Shiga toxin- HUS - Less than 2 years old - Respiratory distress, neurologic involvement, and coma. Neuraminidase -HUS - Occurs primarily in children, (except in epidemics with any age) -Watery or bloody diarrhoea. - Stool Culture: detection of E. coli O157:H7 and other STEC and their products in stool cultures (sorbitol-containing MacConkey agar - SMAC) Mead PS, Griffin PM. Lancet. 1998;352:1207-1212. 18
  58. 58. Systematic Approach of Diagnosis Atypical HUS TTP Step 5 – TTP vs HUS Shiga toxin- HUS Neuraminidase -HUS 19
  59. 59. Systematic Approach of Diagnosis Step 5 – TTP vs HUS Atypical HUS TTP Difficult to distinguish on clinical grounds only Moschcowitz E. Mt Sinai J Med. 2003;70:352-355. 19
  60. 60. Systematic Approach of Diagnosis Step 5 – TTP vs HUS Atypical HUS TTP Difficult to distinguish on clinical grounds only TTP Pentad: 1. Microangiopathic haemolytic anaemia 2. Thrombocytopenia with purpura 3. Acute renal insufficiency 4. Neurological abnormalities 5. Fever is rare for all of these features (TTP pentad) to be seen. 19 -Vesely SK et al. Blood. 2003;102:60-68. -Marie Scully et al. British Journal of Haematology, 2012, 158, 323–335.
  61. 61. Systematic Approach of Diagnosis Step 5 – TTP vs HUS Atypical HUS TTP Difficult to distinguish on clinical grounds only Differential diagnosis of aHUS is made on exclusion: • Of infections by STEC or neuraminidase - producing S.pneumoniae, • Of ADAMTS13 deficiency, • Of Systemic-associated diseases 20
  62. 62. Systematic Approach of Diagnosis Step 5 – TTP vs HUS Atypical HUS TTP Difficult to distinguish on clinical grounds only Moschcowitz E. Mt Sinai J Med. 2003;70:352-355. Eknoyan G, Riggs SA. Am J Nephrol. 1986;6:117-131. 20
  63. 63. Systematic Approach of Diagnosis Step 1: Exclusion of drugs Step 2: Exclusion of Autoimmune hemolysis Step 3: Coagulation Profile Step 4: Exclusion of other systemic causes Step 5: TTP vs HUS? 20
  64. 64. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 21
  65. 65. Questions What is meant by Thrombotic Microangiopathy (TMA)? What are the causes of TMA? What is the mechanism of TMA in TTP-HUS? What is the diagnostic approach of TTP-HUS & TMA? What are the treatment protocols of TTP-HUS? 21
  66. 66. Shiga Toxin Associated HUS E. coli (STEC) S. dysenteriae watery or most often bloody diarrhea Morigi M et al. Blood. 2001;98:1828-1835. Morigi M et al. J Immunol. 2011;187:172-180. 21
  67. 67. Shiga Toxin Associated HUS Treatment Generally Supportive (including RRT if required) No role for anticoagulation No role for Antitimotility agents 21
  68. 68. Shiga Toxin Associated HUS Treatment Generally Supportive (including RRT if required) No role for Antibiotics except: 1.Patients presenting with bacteremia 2.HUS, hemorrhagic colitis and HUS caused by Shigella dysentery type 1 3.Azithromycin had some benefit on the duration of bacterial shedding in adult patients from the German O104:H4 epidemic 21
  69. 69. Shiga Toxin Associated HUS Treatment Generally Supportive (including RRT if required) Is there a role for plasma exchange? No prospective RCTs are available But comparative analyses of two large series of patients treated or not treated with plasma suggest that plasma therapy may dramatically decrease overall mortality of STEC O157:H7–associated HUS. Dundas S et al. Lancet. 1999;354:1327-1330. Carter AO et al. N Engl J Med. 1987;317:1496-1500. 22
  70. 70. Atypical HUS Mutations or Antibodies Caprioli J et al. Blood. 2006;108:1267-1279. Manuelian T, et al. J Clin Invest. 2003;111:1181-1190. 22
  71. 71. Atypical HUS Treatment Plasma exchange vs Plasma infusion Plasma Exchange is superior to Infusion: 1.Plasma exchange allows supplying larger amounts of plasma than would be possible with infusion while avoiding fluid overload. 2.Remission and prevention of recurrences, by removal of mutant CFH. 3.Plasma exchange is used to remove anti-CFH antibodies, but the effect is usually transient. Noris M, Remuzzi G. N Engl J Med. 2009;361:1676-1687. Dragon-Durey MA, et al. J Am Soc Nephrol. 2005;16:555-563. 23
  72. 72. Atypical HUS Treatment Plasma exchange Immunosuppressants (corticosteroids and azathioprine or mycophenolate mofetil) combined with plasma exchange allowed long-term dialysis-free survival in 60% to 70% of patients. Dragon-Durey MA et al. J Am Soc Nephrol. 2010;21:2180-2187. 24
  73. 73. Atypical HUS Treatment Licht C et al. J Am Soc Nephrol. 2011;22:197A. Greenbaum LA et al. J Am Soc Nephrol. 2011;22:197A. 24
  74. 74. HUS Treatment 24 STEC - HUS Atypical HUS • General supportive • No anticoagulation • No antimotility drugs • No antibiotics (except some situations) • ??? PEX • Plasma Therapy (PEX is better) + Immunosuppressives • Eculizmab
  75. 75. TTP - Classification - H-M Tsai. Kidney International (2006) 70, 16–23. -Tsai HM. Annu Rev Med 2006; 57: 419–436. - Allford SL et al. Br J Haematol. 2003;120:556-573. 25 ADAMTS13 activity < 5%, absence of Abs to ADAMTS13.
  76. 76. Acquired TTP Treatment First Line Therapy 25
  77. 77. Acquired TTP Treatment First Line Therapy 25
  78. 78. What is the ideal time to start PEX sessions? 25 Acquired TTP Treatment First Line Therapy
  79. 79. What is the ideal initial volume of exchange? X plasma 5·1 volume (PV) exchange on the first 3 d followed by 1·0 PV exchange thereafter Canadian ( apheresis trial )regimen 26 Acquired TTP Treatment First Line Therapy
  80. 80. When to intensify PEX? 1. Refractory TTP (Progression of clinical symptoms or persistent thrombocytopenia despite seven daily PEX procedures) 2. New neurological insult 3. New cardiac insult 26 Acquired TTP Treatment First Line Therapy
  81. 81. When to stop PEX? 27 Acquired TTP Treatment First Line Therapy
  82. 82. When Plasma infusion is indicated? Although PEX remains the treatment of choice, large volume plasma infusions are indicated if there is to be a delay in arranging PEX. 27 Acquired TTP Treatment First Line Therapy Pereira A, Mazzara R, Monteagudo J, et al. Ann Hematol. 1995;70:319-323.
  83. 83. First line within 4-6 hrs )volume exchange( Highly recommended ?? although no RCT If platelets > 50 Specially when hemolysis /Clinical situation Hemolysis Only if !!!! sever bleeding ?? If platelets > 50 ?When to intensify ?When to stop 28 Acquired TTP Treatment First Line Therapy
  84. 84. Acquired TTP Treatment Other Options 29
  85. 85. Acquired TTP Treatment Other Options 29 Refractory ??TTP Relapse ??TTP
  86. 86. Refractory/ Relapsing TTP 29 Refractory TTP: Progression of clinical symptoms or persistent thrombocytopenia despite seven daily PEX procedures Relapsing TTP: Episode of acute TTP more than 30 d after remission, and occurs in 20–50% of cases.
  87. 87. Refractory TTP 29
  88. 88. Relapsing TTP 29
  89. 89. 30 Acquired TTP Treatment Other Options
  90. 90. Refractory/ - Resistant Cases Initiation - (cardiac, )neurological Case Reports & small trials but recommended ?? Trials 30 Acquired TTP Treatment Other Options
  91. 91. TTP - First described Dr. Eli Moschcowitz Arch Intern . Med. 1925;36:89 30
  92. 92. To download the lecture with full animations please contact me on drgawad@gmail.com
  93. 93. Gawad Thank You

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