Thrombotic Thrombocytopenic Purpura - TTP (Take Home Messages)

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Thrombotic Thrombocytopenic Purpura - TTP :

Thrombotic Thrombocytopenic Purpura - TTP Mohammed Abdel Gawad Nephrology Specialist Kidney & Urology Center (KUC) Alexandria - Egypt drgawad@gmail.com Take Home Messages

TTP - First described:

TTP - First described Dr. Eli Moschcowitz Arch Intern Med. 1925;36:89.

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Pathogenesis & Classification

What is vWF role in body?:

What is vWF role in body? It acts as a carrier protein for factor II. It facilitates platelets aggregation and adhesion to damaged blood vessels. It enhances deposition of fibrin. None of the above. - Flora Peyvandi et al. Blood Transfus 2011; 9 Suppl 2:s3-s8 DOI 10.2450/2011.002S - Romijn RAP et al. J Biol Chem 2001; 276: 9985-91. - Leo T. Kroonen et al. Orthopedics. March 2008 - Volume 31 ·

What is vWF role in body?:

- Flora Peyvandi et al. Blood Transfus 2011; 9 Suppl 2:s3-s8 DOI 10.2450/2011.002S - Romijn RAP et al. J Biol Chem 2001; 276: 9985-91. - Leo T. Kroonen et al. Orthopedics. March 2008 - Volume 31 · What is vWF role in body? vWF activation = Platelets Aggregation & Adhesion

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What is ADAMTS 13, and What is its role? It cleaves fibrin formed clots. It cleaves endothelial vWF large multimers . It has an important role in blood clot formation. None of the above. - H-M Tsai. Kidney International (2006) 70, 16–23. - Tsai HM. Annu Rev Med 2006; 57: 419–436.

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H-M Tsai. Kidney International (2006) 70, 16–23. What is ADAMTS 13, and What is its role?

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Platelets vWF ADAMTS 13 - www.nephrotube.blogspot.com H-M Tsai. Kidney International (2006) 70, 16–23. - Tsai HM. Annu Rev Med 2006; 57: 419–436. What is ADAMTS 13, and What is its role?

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Platelets vWF ADAMTS 13 - www.nephrotube.blogspot.com H-M Tsai. Kidney International (2006) 70, 16–23. - Tsai HM. Annu Rev Med 2006; 57: 419–436. Absence of or Abs to ADAMTS 13 → Persistent vWF large multimers → Platelets microthrombi What is ADAMTS 13, and What is its role?

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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.

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- 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. Idiopathic Secondary (see later) TTP - Classification

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TTP – Thrombus Constituents Microthrombus in TTP is mainly formed of: Platelets Fibrin Fibrin and Platelets Platelets and vWF None of the above Microthrombi TTP are not formed of fibrin Bianchi V et al. Blood. 2002;100:710-713.

TTP – MAHA :

TTP – MAHA

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Clinical Presentation & Differential Diagnosis

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TTP – Presentation Which of the following is SPECIFIC or Pathognomonic for TTP: Microangiopathic haemolytic anaemia Thrombocytopenia with purpura Acute renal insufficiency Neurological abnormalities Fever None of the above

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It is rare for all of these features (TTP pentad ) to be seen. Diagnosis should be suspected in any patient with thrombocytopenia and MAHA (TTP is not the only cause!!) . Vesely SK et al. Blood. 2003;102:60-68. Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335. TTP – Presentation

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TTP – Deferential Diagnosis Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335. , HIV DD of thrombocytopenia & MAHA

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TTP – Deferential Diagnosis Step 1 – Exclude Drugs Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335.

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Piero Ruggenenti , Comprehensive Clinical Nephrology. 4 th edition, chapter 28, p353 TTP – Deferential Diagnosis Step 1 – Exclude Drugs

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TTP – Deferential Diagnosis Step 1 – Exclude Drugs

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Which of the following coincides with TTP: thrombocytopenia, high LDH, bilirubin and reticulocytes with: - ve Coomb’s test + ve Coomb’s test TTP – Deferential Diagnosis Step 2 – Autoimmune Hemolysis Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335. Patton JF et al. Am J Hematol . 1994;47:94-99.

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Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335. Patton JF et al. Am J Hematol . 1994;47:94-99. TTP – Deferential Diagnosis Step 2 – Autoimmune Hemolysis

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Schistocytes TTP – Deferential Diagnosis Step 2 – Autoimmune Hemolysis

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Which of the following coincides with TTP: thrombocytopenia, high LDH, bilirubin and reticulocytes with: Prolonged PT, High FDP, - ve Coomb’s test Prolonged PT, Normal FDP, - ve Coomb’s test Normal PT/PTT/INR, - ve Coomb’s test Normal PT/PTT/INR, + ve Coomb’s test TTP – Deferential Diagnosis Step 3 – Coagulation Profile

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TTP – Deferential Diagnosis Step 3 – Coagulation Profile

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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 . TTP – Deferential Diagnosis Step 4 – Exclude Other Causes

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DD Suggestive Criteria Sepsis Sepsis patients have hypotension More pronounced f ever 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 TTP – Deferential Diagnosis Step 4 – Exclude Other Causes

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, HIV Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335. TTP – Deferential Diagnosis Step 4 – Exclude Other Causes

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Marie Scully et al. British Journal of Haematology , 2012, 158, 323–335. TTP – Deferential Diagnosis Step 4 – Exclude Other Causes

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TTP – Deferential Diagnosis Final Approach 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

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Which of the following is SPECIFIC or Pathognomonic for TTP: Thrombocytopenia Normal FDP Normal PT/PTT/INR - ve Coomb’s test Schistocytes None of the above There is no pathognomic laboratory test finding, and the diagnosis is made through a combination of factors TTP – Deferential Diagnosis

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ADAMTS 13 Is it recommended to measure ADAMTS 13 Ag level, activity & anti ADAMTS 13 Ab before starting management? Yes No

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Is it essential to hold management ( plasmapharesis ) till results of ADAMTS 13 investigations appear? Yes No Do not wait for result before starting treatment in suspected TTP ADAMTS 13

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Which of the following is characteristic for Congenital TTP? ADAMTS13 activity > 5%, absence of Abs to ADAMTS13. ADAMTS13 activity < 5%, presence of Abs to ADAMTS13. ADAMTS13 activity < 5%, absence of Abs to ADAMTS13. None of the above ADAMTS 13

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Management

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What is the first line of treatment of acute aquired TTP? PEX PEX + CST Immunosuppressive drugs Rituximab Splenectomy Management First Line of Therapy PEX has reduced mortality rates from over 90% to 10–20% von Baeyer H. Ther Apher 2002; 6:320 ?

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Management First Line of Therapy

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Management Second & Third Line of Therapy

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Management First Line of Therapy

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Management When to start PEX? What is the ideal time to start PEX sessions? After confirming diagnosis by ADAMTS 13 After first 24 hrs to ensure heamodynamic status of the patient Within 4 - 8 hrs of diagnosis No available recommendation for when to start PEX

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Which of the following plasma volume exchange is indicated to be urgently initiated ? 1 plasma volume exchange 1.5 plasma volume exchange 2 plasma volume exchange 3 plasma volume exchange It doesn’t matter, any of the above may be used Management Plasma volume Exchange

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Management Plasma volume Exchange 1·5 X plasma volume (PV) exchange on the first 3 d followed by 1·0 PV exchange thereafter (Canadian apheresis trial regimen)

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Management PEX – When to Intensify? Which of the following is an indication for intensification of PEX (e.g. twice daily PEX): Resistant TTP New neurological insult New cardiac insult All of the above

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Management PEX – When to Stop? When to stop PEX sessions? After normalization of LDH level. After normalization of Bilirubin level. Immediately when platelet count > 150 X 10 9 /l Two days after stabilization of platelet count > 150 X 10 9 /l

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Which is considered as the best for Aquired TTP management ? Plasma exchange Plasma exchange Plasma exchange Plasma exchange Management Plasma Exchange vs Infusion Plasma Exchange Always First What is the evidence?

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Management Plasma Exchange vs Infusion Rock GA et al. N Engl J Med. 1991;325:393-397.

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Management Plasma Exchange vs Infusion

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Management Plasma Exchange vs Infusion Plasma exchange both: removes the inhibitory antibody. supplies replacement ADAMTS13 from the donor plasma. - Rock GA et al. N Engl J Med 1991; 325:393. - Bell WR et al. N Engl J Med 1991; 325:398.

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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 . Management Plasma Exchange vs Infusion

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Management First Line of Therapy

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Management Corticosteroids What is the evidence? (1B)

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Management Corticosteroids There is no randomized controlled trial addressing whether a combination of PEX and corticosteroids is superior to PEX alone. The use of corticosteroids is based on historical evidence that some patients with limited symptoms might respond to corticosteroids alone. Bell WR et ak . N Engl J Med. 1991;325:398-403

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Management First Line of Therapy

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Management Antiplatelet Agents What is the evidence?

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Management Antiplatelet Agents Bobbio-Pallavivini E et al. Haematologica . 1997;82:429-435. But decreased rate of early death in the first 15 d in the antiplatelet - treated group (13·5% vs. 2·8%) The Italian Co-operative Group randomized 72 TTP patients to PEX and steroids with and without aspirin and dipyramidole

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Management Folate

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Management Blood Transfusion

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Management Platelet Transfusion

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Management Thromboprophylaxis The risk of venous thromboembolism in acute TTP but is increased due to immobility and acute illness.

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Management First Line of Therapy 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?

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Management Second & Third Line of Therapy Refractory TTP ?? Relapse TTP??

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Management Refractory TTP - Definition Persistent thrombocytopenia or LDH elevation after a total of seven daily PEX procedures. Progression of clinical symptoms or persistent thrombocytopenia despite seven daily PEX procedures No response to treatment after four full days of standard treatment Paul Coppo et al. Presse Med. 2012; 41: e163–e176. LDH is not however, a reliable marker of disease activity, therefore redefined

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Management Refractory TTP - Management

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Management Relapse - Definition Episode of acute TTP more than 30 d after remission, and occurs in 20–50% of cases. Shumak et al, 1995; Bandarenko & Brecher, 1998; Willis & Bandarenko , 2005

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Management Relapse - Management

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Management Second & Third Line of Therapy

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Management Rituximab What is the evidence?

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Management Rituximab Elliott MA et al. Eur J Haematol . 2009;83:365-372.

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Management Rituximab Elliott MA et al. Eur J Haematol . 2009;83:365-372.

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Management Second & Third Line of Therapy What is the evidence?

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Management Ciclosporin Kierdorf H et al. Ann Intern Med 1993; 118:987.

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Management Ciclosporin c Cataland SR et al. Br J Haematol 2007; 136:146

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Management Second & Third Line of Therapy

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Management Vincristine / Cyclophosphamide There are case reports and small retrospective studies to suggest that vincristine may be temporally associated with platelet recovery in refractory TTP. Support for the use of cyclophosphamide in the treatment of refractory TTP comes from small case reports and the theoretical benefit of immunosuppression . Bobbio-Pallavivini E et al. Haematologica . 1997;82:429-435. Welborn JL et al. Am J Hematol . 1990;35:18-21. O'Connor NT et al. Am J Hematol . 1992;39:234-236. Bird JM et al. Lancet. 1990;336:565-566. Udvardy M et al. Lancet. 1990;336:1508-1509. Strutz F et al. Nephrol Dial Transplant. 1998;13:1320-1321.

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Management Second & Third Line of Therapy

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Management Second & Third Line of Therapy - Refractory/ Resistant Cases - Initiation (cardiac, neurological) Case Reports & small trials but recommended ?? Trials

TTP - Pregnancy:

TTP - Pregnancy

TTP - Pregnancy:

TTP - Pregnancy

TTP - HIV:

TTP - HIV

TTP - Transplantation:

TTP - Transplantation

Team Work:

Team Work Nephrologist S Hematologist S

Essential Reading:

Essential Reading

www.kidneyadvances.com:

www.kidneyadvances.com

www.kidneyadvances.com:

www.kidneyadvances.com

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www.nephrotube.blogspot.com facebook group: NephroTube

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