- Email: [email protected]
Simple diagnosis and treatment algorithm for adult thrombotic microangiopathy
Accepted Manuscript Title: Simple Diagnosis and Treatment Algorithm for Adult Thrombotic Microangiopathy Author: W.F. Clark C. Patriquin C Licht PII: DOI: Reference:
S1473-0502(16)30204-X http://dx.doi.org/doi:10.1016/j.transci.2016.12.018 TRASCI 2111
To appear in: Please cite this article as: W.F.Clark, C.Patriquin, C Licht, Simple Diagnosis and Treatment Algorithm for Adult Thrombotic Microangiopathy, http://dx.doi.org/10.1016/j.transci.2016.12.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Simple Diagnosis and Treatment Algorithm for Adult Thrombotic Microangiopathy
CLARK WF, PATRIQUIN C, LICHT C
London Health Sciences Centre, 800 Commissioners Road East, Canada
PHONE: (519) 685-8361
Fax: (519) 685-8047
CORRESPONDING AUTHOR/ADDRESS:
Name:
Dr William Clark
EMAIL:
[email protected]
1
Simple Diagnosis and Treatment Thrombotic Microangiopathy
Algorithm for
Adult
Why do we need a simple algorithm to diagnose and treat adult thrombotic microangiopathy (TMA)? In the case of TMA we use a simple algorithm to arrive at a diagnosis to provide the correct and potentially lifesaving therapy as soon as possible for individuals suffering from an unexplained thrombocytopenia with hemolytic anemia and end organ dysfunction (TMA) [Ref. 1,2,3]. Unfortunately although there are often clinical differences in their presentation, three different pathophysiologic processes (thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and disseminated intravascular coagulation (DIC)) both primary or secondary to another process or disease can in the individual case produce the same clinical picture but have different diagnoses and benefit from different treatments. [Ref 4, 5, 6, 7, 8, 9, 10, 11] At the present time, one simple test doesn’t diagnose these different disorders. We plan to provide a simple pathway to help differentiate TTP from HUS and DIC to facilitate emergent and specific treatment for those suffering from these entities. At onset we will use the international normalized ratio of thrombin time (INR), partial thromboplastin time (PTT) and fibrinogen levels to identify those with a DIC.[Ref. 7, 12] A prolonged INR , PTT with reduced fibrinogen levels indicates the patients TMA is due to DIC often secondary to sepsis or malignancy The rest of the TMA patients ,(shiga toxin negative if bloody diarrhea) will receive immediate plasma exchange therapy with pathogen inactivated plasma (preferable) and will undergo ADAMTS 13 screening, history and tests to identify some of the secondary TMAs (malignancy, malignant hypertension, stem cell transplant and mitamycin C, STEC HUS) that will not benefit 2
from plasma therapy and those that may (collagen vascular disease, drugs, pancreatitis and antiphospholipid antibody syndrome).[Ref. 4, 13, 14, 15, 16] If the patient’s ADAMTS13 levels are greater than 10% and they don’t respond to plasma therapy after 4 daily exchanges and have no characteristics of a secondary disorder then presume they have aHUS (<5% of TMA) and apply for eculizumab therapy and carry out genetic, and anti-CHF auto antibody testing for aHUS. If the patients ADAMTS 13 is <10% (presumed TTP) or they are > 10% and are thought secondary to drugs, collagen vascular disease or pancreatitis and responding to plasmapheresis continue to treat as TTP. If ADAMTS 13 >10% and unresponsive to specific therapy for secondary cause treat as aHUS. [17, 18, 19, 20, 21, 22, 23] If those with ADAMTS 13 <10% relapse (>30 days) or are refractory TTP (<30 days)[Ref. 24, 25] treat with rituximab and if refractory and continue to progress may need to use a variety of other agents as rescue therapy eg. cyclophosphamide, cyclosporine, vincristine, bortezomib, n- acetyl cysteine and or splenectomy. Summary: In patients with unexplained (no known secondary cause) thrombocytopenia and Coombs negative hemolytic anemia, order ADAMTS 13 testing and treat with plasma exchange (PE) and steroids.
Majority of patients will respond in 5-11 PE
regardless of ADAMTS 13 except those with a malignancy, malignant hypertension, stem cell transplant, mitamycin C. [Ref. 4] If patient does not respond in 4 days of daily aggressive PE and is Shiga toxin negative with ADAMTS13 >10% (R/O secondary TMA) suggest you order genetic and anti-CHF autoantibody testing for aHUS and initiate eculizumab therapy with meningococcal vaccination plus appropriate antibiotic coverage. [Ref. 23] If patient with ADAMTS 13 < 3
10% relapses in 1-30 days after remission they are presumed to have refractory TTP and treat with PE (larger volumes) plus rituximab and steroids. [Ref. 25, 26] If patient is still progressing and ADAMTS 13 <10% employ rescue therapy with either vincristine or cyclophosphamide or bortezomib or cyclosporine or NAC or if they fail book for a splenectomy. [Ref. 27, 28, 29, 30, 31] If the ADAMTS 13 >10% and there is no renal recovery, patient has undiagnosed aHUS and order genetic and anti-CHF autoantibody testing and treat with eculizumab. If the patient with ADAMTS 13 <10% relapses >30 days after remission they have relapsing TTP and almost all will remit with PE + steroids + rituximab.
References: 1) Plasmapheresis for the treatment of kidney diseases. Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Kidney Int. 2016 Nov;90(5):974-984. 2) Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in 2014 – Current Knowledge and Outcomes with Plasma Exchange. Farah M, Hildebrand AM, Huang S, Dammas H and Clark WF. Oncology and Hemotology Review. 2014;10(2):82–9. 3) Attending Rounds: Microangiopathic Hemolytic Uremic Anemia with Renal Insufficiency. Clark WF, Hildebrand A. Clinical J Am Soc Nephrol . 2012; Feb;7(2):342-7. 4) Primary and Secondary Thrombotic Microangiopathy Referred to a Single Plasma Exchange Center for Suspected Thrombotic Thrombocytopenic Purpura: 2000-2011. Dahlan R, Sontrop JM, Li L, Ghadieh O, Clark WF. Am J Nephrol. 2015;41(6):429-37. 5) Thrombotic Thrombocytopenic Purpura: report of 16 cases and reviews of the literature. Amorosi E, Ultman J. Medicine (Baltimore). 1966; 45:139. 6) [Hemolytic-uremic Syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia]. Schweiz Med Wochenschr. 1955;85:905-909 [in German]. 7) Laboratory Abnormalities in thrombotic thrombocytopenic Purpura. Rock G, Kelton JG, Shumack KH, et al. Br J Haematol. 1998; 103:1031-1036.
4
8) Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Nathanson S, Kwon T, Elmaleh M, et al. Clin J Am Soc Nephrol. 2010; 5:1218-1228. 9) The Okalahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS.George JN, Vesely SK, Terrell DR. Semin Hematol. 2004; 41:60-67. 10) Thrombotic Thrombocytopenic Purpura and its look alikes. Baron JM, Baron BW. Clin Adv Hematol Oncol. 2005; 3: 868-874. 11) Thrombotic Microangiopathies: Towardds a Pathophysiology-Based Classification. Coppo P, Veyradier A. Cardiovascular and Haematological Disorders-Drug Targets. 2009; 9: 36-50. 12) Platelet count and prothrombin time help distinguish thrombotic thrombocytopenic Purpura-hemolytic uremic syndrome from disseminated intravascular coagulation in adults. Am J Clini Pathol. 2010; 133: 460-465. 13) Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic Purpura. Rock GA, Shumack KH, Buskard Na et al. N Engl J Med. 1991; 325: 393-397. 14) Antibodies to von Wildebrand factor-cleaving protease in acute thrombotic thrombocytopenic Purpura. TSAi HM, Lian EC. N Engl J Med. 1998; 339:15851594. 15) Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic Purpura and the hemolytic-uremic syndrome. Furlan M, Robles R, Galbusera M, et al. N Engl J Med. 1998; 339: 1578-1584. 16) Von WIllebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Bianchi V, Robles R, Alberio L, et al. Blood. 2002; 100: 710-713. 17) How I treat thrombotic thrombocytopenic Purpura and atypical haemolytic uremic syndrome. Scully M, Goodship T. Br J Haematol. 2014; 164: 759-766. 18) Syndromes of thrombotic microangiopathy. George JN, Nester CM. N Engl J Med. 2014; 371: 654-666. 19) Atypical hemolytic uremic syndrome. Loirat C, Fremeaux-Bacchi V. Orphanet j Rare Dis. 2011; 6:60. 20) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Norris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010; 5: 1844-1859. 21) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Loirat C, Fakhouri F, Ariceta G, et al. Pediatr Nephrol. 2016; 31: 15-39. 22) Terminal complement inhibitor Eculizumab in atypical hemolytic-uremic syndrome. Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013; 368: 2169-2181. 23) The use of ADAMTS13 activity, platelet count, and serum creatinine to differentiate acquired thrombotic thrombocytopenic Purpura from other thrombotic Microangiopathies. Cataland SR, Yang S, Wu HM. Br J Haematol. 2012; 157: 501-503. 5
24) Late relapses in patients successfully treated for thrombotic thrombocytopenic Purpura. Shumack KH, Rock GA, Nair RC, Canadian Apheresis Group. Ann Intern Med. 1995; 122: 569-572. 25) A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic Purpura treated with rituximab. Clark WF, Rock G, Barth D, et al, for the Canadian Apheresis Group. 2015; 170: 208-217. 26) Rituximab for refractory and or relapsing thrombotic thrombocytopenic Purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature. Elliott MA, Heit JA, Pruthi RK, et al. Eur J Haematol. 2009; 83:365-72. 27) Treatment of severe, refractory and rapidly evolving thrombotic thrombocytopenic Purpura. Acedillo RR, Govind M, Kashgary A, Clark WF. BMJ Case Report. 2016; Jun 9;2016. pii: bcr2016215491. doi: 10.1136/bcr-2016-215491. 28) Treatment of refractory thrombotic thrombocytopenic Purpura using multimodality therapy including splenectomy and cyclosporine. Jhaveri KD, Scheuer A, Cohen j, et al. Transfus Apher Sci. 2009; 41: 19-22. 29) ADAMTS13 antibody depletion by Bortezomib in thrombotic thrombocytopenic Purpura. Shortt J, Oh DH, Opat SS. N Engl J Med. 2013; 368: 90-92. 30) N-Acetylcysteine: an old drug, a new insight, a potentially effective treatment for thrombotic thrombocytopenic purpura. George JN, Lopez JA, Konkle BA. Transfusion. 2014; 54: 1205-1207. 31) Frequently relapsing thrombotic thrombocytopenic Purpura treated with cytotoxic immunosuppressive therapy. Allan DS, Kovacs MJ, Clark WF. Haematologica. 2001; 86: 844-50.
6
S1473-0502(16)30204-X http://dx.doi.org/doi:10.1016/j.transci.2016.12.018 TRASCI 2111
To appear in: Please cite this article as: W.F.Clark, C.Patriquin, C Licht, Simple Diagnosis and Treatment Algorithm for Adult Thrombotic Microangiopathy, http://dx.doi.org/10.1016/j.transci.2016.12.018 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Simple Diagnosis and Treatment Algorithm for Adult Thrombotic Microangiopathy
CLARK WF, PATRIQUIN C, LICHT C
London Health Sciences Centre, 800 Commissioners Road East, Canada
PHONE: (519) 685-8361
Fax: (519) 685-8047
CORRESPONDING AUTHOR/ADDRESS:
Name:
Dr William Clark
EMAIL:
[email protected]
1
Simple Diagnosis and Treatment Thrombotic Microangiopathy
Algorithm for
Adult
Why do we need a simple algorithm to diagnose and treat adult thrombotic microangiopathy (TMA)? In the case of TMA we use a simple algorithm to arrive at a diagnosis to provide the correct and potentially lifesaving therapy as soon as possible for individuals suffering from an unexplained thrombocytopenia with hemolytic anemia and end organ dysfunction (TMA) [Ref. 1,2,3]. Unfortunately although there are often clinical differences in their presentation, three different pathophysiologic processes (thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS) and disseminated intravascular coagulation (DIC)) both primary or secondary to another process or disease can in the individual case produce the same clinical picture but have different diagnoses and benefit from different treatments. [Ref 4, 5, 6, 7, 8, 9, 10, 11] At the present time, one simple test doesn’t diagnose these different disorders. We plan to provide a simple pathway to help differentiate TTP from HUS and DIC to facilitate emergent and specific treatment for those suffering from these entities. At onset we will use the international normalized ratio of thrombin time (INR), partial thromboplastin time (PTT) and fibrinogen levels to identify those with a DIC.[Ref. 7, 12] A prolonged INR , PTT with reduced fibrinogen levels indicates the patients TMA is due to DIC often secondary to sepsis or malignancy The rest of the TMA patients ,(shiga toxin negative if bloody diarrhea) will receive immediate plasma exchange therapy with pathogen inactivated plasma (preferable) and will undergo ADAMTS 13 screening, history and tests to identify some of the secondary TMAs (malignancy, malignant hypertension, stem cell transplant and mitamycin C, STEC HUS) that will not benefit 2
from plasma therapy and those that may (collagen vascular disease, drugs, pancreatitis and antiphospholipid antibody syndrome).[Ref. 4, 13, 14, 15, 16] If the patient’s ADAMTS13 levels are greater than 10% and they don’t respond to plasma therapy after 4 daily exchanges and have no characteristics of a secondary disorder then presume they have aHUS (<5% of TMA) and apply for eculizumab therapy and carry out genetic, and anti-CHF auto antibody testing for aHUS. If the patients ADAMTS 13 is <10% (presumed TTP) or they are > 10% and are thought secondary to drugs, collagen vascular disease or pancreatitis and responding to plasmapheresis continue to treat as TTP. If ADAMTS 13 >10% and unresponsive to specific therapy for secondary cause treat as aHUS. [17, 18, 19, 20, 21, 22, 23] If those with ADAMTS 13 <10% relapse (>30 days) or are refractory TTP (<30 days)[Ref. 24, 25] treat with rituximab and if refractory and continue to progress may need to use a variety of other agents as rescue therapy eg. cyclophosphamide, cyclosporine, vincristine, bortezomib, n- acetyl cysteine and or splenectomy. Summary: In patients with unexplained (no known secondary cause) thrombocytopenia and Coombs negative hemolytic anemia, order ADAMTS 13 testing and treat with plasma exchange (PE) and steroids.
Majority of patients will respond in 5-11 PE
regardless of ADAMTS 13 except those with a malignancy, malignant hypertension, stem cell transplant, mitamycin C. [Ref. 4] If patient does not respond in 4 days of daily aggressive PE and is Shiga toxin negative with ADAMTS13 >10% (R/O secondary TMA) suggest you order genetic and anti-CHF autoantibody testing for aHUS and initiate eculizumab therapy with meningococcal vaccination plus appropriate antibiotic coverage. [Ref. 23] If patient with ADAMTS 13 < 3
10% relapses in 1-30 days after remission they are presumed to have refractory TTP and treat with PE (larger volumes) plus rituximab and steroids. [Ref. 25, 26] If patient is still progressing and ADAMTS 13 <10% employ rescue therapy with either vincristine or cyclophosphamide or bortezomib or cyclosporine or NAC or if they fail book for a splenectomy. [Ref. 27, 28, 29, 30, 31] If the ADAMTS 13 >10% and there is no renal recovery, patient has undiagnosed aHUS and order genetic and anti-CHF autoantibody testing and treat with eculizumab. If the patient with ADAMTS 13 <10% relapses >30 days after remission they have relapsing TTP and almost all will remit with PE + steroids + rituximab.
References: 1) Plasmapheresis for the treatment of kidney diseases. Clark WF, Huang SS, Walsh MW, Farah M, Hildebrand AM, Sontrop JM. Kidney Int. 2016 Nov;90(5):974-984. 2) Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome in 2014 – Current Knowledge and Outcomes with Plasma Exchange. Farah M, Hildebrand AM, Huang S, Dammas H and Clark WF. Oncology and Hemotology Review. 2014;10(2):82–9. 3) Attending Rounds: Microangiopathic Hemolytic Uremic Anemia with Renal Insufficiency. Clark WF, Hildebrand A. Clinical J Am Soc Nephrol . 2012; Feb;7(2):342-7. 4) Primary and Secondary Thrombotic Microangiopathy Referred to a Single Plasma Exchange Center for Suspected Thrombotic Thrombocytopenic Purpura: 2000-2011. Dahlan R, Sontrop JM, Li L, Ghadieh O, Clark WF. Am J Nephrol. 2015;41(6):429-37. 5) Thrombotic Thrombocytopenic Purpura: report of 16 cases and reviews of the literature. Amorosi E, Ultman J. Medicine (Baltimore). 1966; 45:139. 6) [Hemolytic-uremic Syndrome: bilateral necrosis of the renal cortex in acute acquired hemolytic anemia]. Schweiz Med Wochenschr. 1955;85:905-909 [in German]. 7) Laboratory Abnormalities in thrombotic thrombocytopenic Purpura. Rock G, Kelton JG, Shumack KH, et al. Br J Haematol. 1998; 103:1031-1036.
4
8) Acute neurological involvement in diarrhea-associated hemolytic uremic syndrome. Nathanson S, Kwon T, Elmaleh M, et al. Clin J Am Soc Nephrol. 2010; 5:1218-1228. 9) The Okalahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS) Registry: a community perspective of patients with clinically diagnosed TTP-HUS.George JN, Vesely SK, Terrell DR. Semin Hematol. 2004; 41:60-67. 10) Thrombotic Thrombocytopenic Purpura and its look alikes. Baron JM, Baron BW. Clin Adv Hematol Oncol. 2005; 3: 868-874. 11) Thrombotic Microangiopathies: Towardds a Pathophysiology-Based Classification. Coppo P, Veyradier A. Cardiovascular and Haematological Disorders-Drug Targets. 2009; 9: 36-50. 12) Platelet count and prothrombin time help distinguish thrombotic thrombocytopenic Purpura-hemolytic uremic syndrome from disseminated intravascular coagulation in adults. Am J Clini Pathol. 2010; 133: 460-465. 13) Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic Purpura. Rock GA, Shumack KH, Buskard Na et al. N Engl J Med. 1991; 325: 393-397. 14) Antibodies to von Wildebrand factor-cleaving protease in acute thrombotic thrombocytopenic Purpura. TSAi HM, Lian EC. N Engl J Med. 1998; 339:15851594. 15) Von Willebrand factor-cleaving protease in thrombotic thrombocytopenic Purpura and the hemolytic-uremic syndrome. Furlan M, Robles R, Galbusera M, et al. N Engl J Med. 1998; 339: 1578-1584. 16) Von WIllebrand factor-cleaving protease (ADAMTS13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Bianchi V, Robles R, Alberio L, et al. Blood. 2002; 100: 710-713. 17) How I treat thrombotic thrombocytopenic Purpura and atypical haemolytic uremic syndrome. Scully M, Goodship T. Br J Haematol. 2014; 164: 759-766. 18) Syndromes of thrombotic microangiopathy. George JN, Nester CM. N Engl J Med. 2014; 371: 654-666. 19) Atypical hemolytic uremic syndrome. Loirat C, Fremeaux-Bacchi V. Orphanet j Rare Dis. 2011; 6:60. 20) Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Norris M, Caprioli J, Bresin E, et al. Clin J Am Soc Nephrol. 2010; 5: 1844-1859. 21) An international consensus approach to the management of atypical hemolytic uremic syndrome in children. Loirat C, Fakhouri F, Ariceta G, et al. Pediatr Nephrol. 2016; 31: 15-39. 22) Terminal complement inhibitor Eculizumab in atypical hemolytic-uremic syndrome. Legendre CM, Licht C, Muus P, et al. N Engl J Med. 2013; 368: 2169-2181. 23) The use of ADAMTS13 activity, platelet count, and serum creatinine to differentiate acquired thrombotic thrombocytopenic Purpura from other thrombotic Microangiopathies. Cataland SR, Yang S, Wu HM. Br J Haematol. 2012; 157: 501-503. 5
24) Late relapses in patients successfully treated for thrombotic thrombocytopenic Purpura. Shumack KH, Rock GA, Nair RC, Canadian Apheresis Group. Ann Intern Med. 1995; 122: 569-572. 25) A phase-II sequential case-series study of all patients presenting to four plasma exchange centres with presumed relapsed/refractory thrombotic thrombocytopenic Purpura treated with rituximab. Clark WF, Rock G, Barth D, et al, for the Canadian Apheresis Group. 2015; 170: 208-217. 26) Rituximab for refractory and or relapsing thrombotic thrombocytopenic Purpura related to immune-mediated severe ADAMTS13-deficiency: a report of four cases and a systematic review of the literature. Elliott MA, Heit JA, Pruthi RK, et al. Eur J Haematol. 2009; 83:365-72. 27) Treatment of severe, refractory and rapidly evolving thrombotic thrombocytopenic Purpura. Acedillo RR, Govind M, Kashgary A, Clark WF. BMJ Case Report. 2016; Jun 9;2016. pii: bcr2016215491. doi: 10.1136/bcr-2016-215491. 28) Treatment of refractory thrombotic thrombocytopenic Purpura using multimodality therapy including splenectomy and cyclosporine. Jhaveri KD, Scheuer A, Cohen j, et al. Transfus Apher Sci. 2009; 41: 19-22. 29) ADAMTS13 antibody depletion by Bortezomib in thrombotic thrombocytopenic Purpura. Shortt J, Oh DH, Opat SS. N Engl J Med. 2013; 368: 90-92. 30) N-Acetylcysteine: an old drug, a new insight, a potentially effective treatment for thrombotic thrombocytopenic purpura. George JN, Lopez JA, Konkle BA. Transfusion. 2014; 54: 1205-1207. 31) Frequently relapsing thrombotic thrombocytopenic Purpura treated with cytotoxic immunosuppressive therapy. Allan DS, Kovacs MJ, Clark WF. Haematologica. 2001; 86: 844-50.
6