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Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad
The document discusses thrombotic microangiopathy (TMA) and its implications in thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS). It outlines the causes, mechanisms, diagnostic approaches, and treatment protocols related to TTP and TMA. Additionally, it emphasizes the importance of distinguishing TTP from related conditions through systematic diagnosis.
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Thrombotic Thrombocytopenic Purpura / Hemolytic Uremic Syndrome (Questions & Answers) - Dr. Gawad
- 1. TTP/HUS r Questions& Answers Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria [email protected] ESNT Outreach Program, Sohag, December 4-7, 2014
- 2. To download thelecture with full animations please contact me on [email protected]
- 3. Questions What ismeant 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. Questions What ismeant 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. What is meantby Thrombotic Microangiopathy (TMA)? Intraluminal platelet thrombosis Thrombocytopenia Microangiopathic hemolytic anemia Consumption of platelets Hemolysis, Anemia, ↑LDH & Bilirubin 1
- 6. Questions What ismeant 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. Questions What ismeant 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. What are thecauses of ?TMA HIV, TTP/HUS 2
- 9. Questions What ismeant 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. Questions What ismeant 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. What is themechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Thrombocytopenia Microangiopathic hemolytic anemia Consumption of platelets Hemolysis, Anemia, ↑LDH & Bilirubin 2
- 12. What is themechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS Neuraminidase HUS Atypical HUS 3
- 13. What is themechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS Neuraminidase HUS Atypical HUS 3
- 14. What is vWFrole 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. What is vWFrole 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
- 23. 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
- 24. What is themechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS 6
- 25. What is themechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Consumption of platelets Thrombocytopenia TTP Shiga toxin HUS ADAMTS 13 Neuraminidase HUS Atypical HUS 6
- 26. Shiga Toxin AssociatedHUS 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
- 27. Shiga Toxin AssociatedHUS 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
- 28. Shiga Toxin AssociatedHUS 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
- 29. Shiga Toxin AssociatedHUS 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
- 30. What is themechanism 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
- 31. What is themechanism 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
- 32. 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
- 33. 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
- 34. 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
- 35. What is themechanism 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
- 36. What is themechanism 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
- 37. Atypical HUS Lowserum 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
- 38. Atypical HUS CaprioliJ et al. Blood. 2006;108:1267-1279. Manuelian T, et al. J Clin Invest. 2003;111:1181-1190. 9
- 39.
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- 41. Atypical HUS Acquireddefects 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
- 42.
- 43. What is themechanism 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
- 44. What is themechanism of TMA in TTP-HUS? Intraluminal platelet thrombosis Thrombocytopenia Microangiopathic hemolytic anemia Consumption of platelets Hemolysis, Anemia, ↑LDH & Bilirubin 11
- 45. TTP – MAHA 11
- 46. To download thelecture with full animations please contact me on [email protected]
- 47. Questions What ismeant 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
- 48. Questions What ismeant 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
- 49. Marie Scully etal. British Journal of Haematology, 2012, 158, 323– 335. HIV, DD of thrombocytopenia & MAHA Systematic Approach of Diagnosis 12
- 50. Systematic Approach MarieScully et al. British Journal of Haematology, 2012, 158, 323– 335. of Diagnosis Step 1 – Exclude Drugs 12
- 51. Systematic Approach PieroRuggenenti, Comprehensive Clinical Nephrology. 4th edition, chapter 28, p353 of Diagnosis Step 1 – Exclude Drugs 12
- 52. Systematic Approach ofDiagnosis Step 1 – Exclude Drugs Step 1 – Exclude Drugs 12
- 53. Systematic Approach ofDiagnosis - 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
- 54. Systematic Approach ofDiagnosis - 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
- 55. Systematic Approach ofDiagnosis - 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
- 56. Systematic Approach ofDiagnosis Step 3 – Coagulation Profile Step 4 – Exclude other causes 14
- 57. Systematic Approach ofDiagnosis 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
- 58. Systematic Approach ofDiagnosis 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
- 59. Systematic Approach ofDiagnosis Step 4 – Exclude other causes HIV, 17
- 60. Systematic Approach ofDiagnosis Step 4 – Exclude other causes 17
- 61. Systematic Approach ofDiagnosis 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
- 62. Systematic Approach ofDiagnosis Atypical HUS TTP Step 5 – TTP vs HUS Shiga toxin- HUS Neuraminidase -HUS 18
- 63. Systematic Approach ofDiagnosis 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
- 64. Systematic Approach ofDiagnosis 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
- 65. Systematic Approach ofDiagnosis Atypical HUS TTP Step 5 – TTP vs HUS Shiga toxin- HUS Neuraminidase -HUS 19
- 66. Systematic Approach ofDiagnosis 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
- 67. Systematic Approach ofDiagnosis 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.
- 68. Systematic Approach ofDiagnosis 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
- 69. Systematic Approach ofDiagnosis 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
- 70. Systematic Approach ofDiagnosis 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
- 71. Questions What ismeant 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
- 72. Questions What ismeant 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
- 73. Shiga Toxin AssociatedHUS 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
- 74. Shiga Toxin Associated HUS Treatment Generally Supportive (including RRT if required) No role for anticoagulation No role for Antitimotility agents 21
- 75. 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
- 76. 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
- 77. Atypical HUS Mutationsor Antibodies Caprioli J et al. Blood. 2006;108:1267-1279. Manuelian T, et al. J Clin Invest. 2003;111:1181-1190. 22
- 78. 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
- 79. 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
- 80. 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
- 81. 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
- 82. 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.
- 83. Acquired TTP Treatment First Line Therapy 25
- 84. Acquired TTP Treatment First Line Therapy 25
- 85. What is theideal time to start PEX sessions? 25 Acquired TTP Treatment First Line Therapy
- 86. What is theideal 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
- 87. When to intensifyPEX? 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
- 88. When to stopPEX? 27 Acquired TTP Treatment First Line Therapy
- 89. When Plasma infusionis 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.
- 90. First line within4-6 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
- 91. Acquired TTP Treatment Other Options 29
- 92. Acquired TTP Treatment Other Options 29 Refractory ??TTP Relapse ??TTP
- 93. 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.
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- 95.
- 96. 30 Acquired TTPTreatment Other Options
- 97. Refractory/ - ResistantCases Initiation - (cardiac, )neurological Case Reports & small trials but recommended ?? Trials 30 Acquired TTP Treatment Other Options
- 98. TTP - Firstdescribed Dr. Eli Moschcowitz Arch Intern . Med. 1925;36:89 30
- 99. To download thelecture with full animations please contact me on [email protected]
- 100.