Thrombotic Thrombocytopenic Purpura.Yesterday, Today and Tomorrow
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Thrombotic Thrombocytopenic Purpura...Yesterday, Today and Tomorrow Leo J. McCarthy, MD, FRCP Edin/IreProfessor of Pathology, Medicine, and Pediatrics Jeffrey S. Dlott, MD Constance F.M. Danielson, MD, PhD Department of Pathology
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Thrombotic Thrombocytopenic Purpura History: Dr. Eli Moschcowitz – 1924, NYC(Arch Intern Med 31:89, 1925) 16 yo girl with weakness, joint pain, 40°C fever, hemolytic anemia, WBC, no platelet count; 4 days paresis (L), coma, death "Acute febrile pleiochromic anemia associated with widespread microvascular occlusive thrombi"
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Incidence Rates(Torok et al. Am J Hematol 1995;50:84) In 1991, 1.1 per million per year Estimate current, 3.7 per million per year Case-specific mortality independent of age, sex, race
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TTP/HUS Clinical Syndromes of Microangiopathic Hemolytic Anemia (MAHA)
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Changes in Clinical Spectrum HIV-1 associated: Response rate (increased platelets) comparable to idiopathic, but mortality higher Drug-induced: CSA, FK506, quinine, mitomycin C, Ticlopidine (RR ratio 50, 1/1600 to 1/5000 treated patients) BMT: CSA, FK506
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Mortality in TTP Cardiac Arrest Microvascular occlusion of the vessels serving the conduction system Most common cause of death at presentation Also occurs with premature withdrawal of treatment Multi-system Organ Failure/Sepsis The intensive care syndrome Two or more weeks of therapy
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Fatal Platelet Thrombi in CNS
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Diagnosis Classical Pentad Thrombocytopenia usually profound, little/no bleeding Microangiopathic hemolytic anemia may be mild, few schistocytes Neurologic dysfunction typically fluctuating Renal dysfunction mild azotemia, not overt failure Fever in @ 80%
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Diagnosis of TTP Minimum Criteria Thrombocytopenia Microangiopathic hemolysis Elevated LDH No evidence of DIC Helpful Extras Neurologic and renal dysfunction, fever
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Pathophysiology of TTP Endothelial Cell Death Laurence et al. Plasma from patients with idiopathic and human immunodeficiency virus-associated thrombotic thrombocytopenic purpura induces apoptosis in microvascular endothelial cells. Blood 1996;87:3245. Does not induce apoptosis of endothelial cells derived from large vessels.
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Pathophysiology of TTP Unusually Large von Willebrand Multimers Moake et al. New Eng J Med 1982;307:1432. Associated with chronic relapsing variant of TTP Relationship not confirmed by others Possible marker of endothelial cell damage
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Pathophysiology Moake, J Clin Apher 13:126-132 (1998) Endothelial Cell-derived ULvWf Multimers Normal PlasmavWf Multimers Reductase vWf Metalloproteinase TTP Smaller vWf Multimers and Fragments
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Changes of the von Willebrand factor cleaving protease activity in various clinical conditions TTP Acute sporadic or chronic relapsing ???? AGING ? Transplantation-associated N NEWBORNS ??? Ticlopidine- or Clopidogrel-associated ??? PREGNANCY ?? Cancer-associated ??? CIRRHOSIS ??? HUS UREMIA ?? Acute sporadic N INFLAMMATION ??? Chronic relapsing ???? POST-OPERATIVE PERIOD ?? N denotes normal levels
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Adult TTP/HUS Clinically still considered a continuum of clinical manifestations requiring plasma exchange for presumptive diagnosis. Pathophysiology may be different: TTP due to hereditary or autoimmune antibody-induced plasma metalloproteinase deficiency; HUS has normal vWF processing protease.
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Platelet Transfusions in Acute TTP Platelet transfusion relatively contraindicated Anecdotal evidence that platelet transfusion associated with acute clinical deterioration Avoid except when needed for serious bleeding
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TTP Medical Research Group (1983)13 Centers Worldwide - 100 Patients Standardized Treatment: Plasma exchange 60 ml/kg/day Vincristine 2 mg IV, day 1 1 mg IV days 4, 7, 10 Methylprednisolone 0.75 mg/kg IV q 12 hrs Extend 2 days beyond complete remission Blood 1990;76(1):508A
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Plasma Infusion vs. Plasma Exchange Rock et al. NEJM 325(6): 396 0 5 10 15 20 25 30 1 0.8 0.6 0.4 0.2 0 Weeks Proportion Surviving Plasma exchange Plasma infusion
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Management Plasma Infusion vs. Exchange Rock et al. NEJM, Aug 1991 Randomized trial 102 pts, PE vs. PI All pts received ADA/dipyridamole and no steroids 6m mortality PE: 22% PI: 37%
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Plasma Infusion vs. Exchange PE superior to infusion Canadian Apheresis Trial But, unequal volumes of plasma infused Rock GA, Shumak KH, Buskard NA, et al: Comparison of plasma exchange with plasma infusion. N Eng J Med 1991;325:393-7 No prospective trials
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Survival Rate(161 TTP Patients) Deceased (33)20% Alive (128)80%
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Males vs. Females(161 TTP Patients) Males (55)34% Females (106)66%
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Mortality and Recurrence on Survivors(161 TTP Patients) Alive -No Recurrence (100)63% Deceased (33)20% Alive -Recurrence (28)17%
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Mortality Rate Comparison(161 TTP Patients) 32 3 34 14 47 15 15 1
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Recurrence vs. No RecurrenceTTP PatientsClarian Health Partners 53 9 50 3 31 3
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Average and Median # ProceduresTTP PatientsClarian Health Partners 10 8.4 19.5 25.1 10 16.9
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Should Splenectomy Still Have a Role in the Treatment of Patients with Refractory TTP?
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Methods Between 1982 and 1998, 15 of 73 patients failed to respond adequately to intensive PE therapy and underwent splenectomies. Their clinical responses to splenectomy and their eventual outcomes were analyzed.
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The spleens were carefully examined for thrombi and subendothelial deposits as well as for trilineage extramedullary hematopoiesis by morphology and immunohistochemistry for Factor VIII:RAg, myeloperoxidase, and hemoglobin.
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Microthrombi composed of fibrin and platelets are difficult to demonstrate and are found inconsistently although they have been regarded as the pathognomic lesion since 1936. Subendothelial deposits in small vessels may be more frequent but are less specific.
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Splenectomy for TTP
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Results None of the 15 patients died secondary to splenectomy. To our knowledge, 9 patients are still alive and none have relapsed. Nine spleens were enlarged with mean weights of 213 ± 70 g (median 193 g; range 150 to 392 g). Ten spleens displayed thrombi/ subendothelial deposits and 11 spleens exhibited extramedullary hematopoiesis, mostly erythropoiesis.
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Intrasplenic platelet destruction may have a significant role in the pathogenesis of TTP in some patients and splenectomy may, therefore, be beneficial to these patients.
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TTP Patients Who Had Splenectomy Deceased (6) Alive (10)
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Conclusion Definitive histopathologic changes in the majority of these spleens support the therapeutic beneficial role of splenectomy for some patients.
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Desperation Vincristine: 2 mg IV, 3 doses over 5-7 days Splenectomy IV immunoglobulin Cyclophosphamide Cyclosporin Beware concomitant sepsis McCarthy, Trans 1998; 38:7S.
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ADAMTS 13 A Disintegrin-like And Metalloprotease with ThromboSpondin-1 repeats
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Assays Quantitative Immunoblotting of Degraded vWF Residual Collagen Binding (vWF:CB) Ristocetin Cofactor Activity (vWF:RCo) of Degraded vWF Two-site Immunoradiometric Assay with Monoclonal Antibodies to C- and N-terminal Regions of the vWF subunit
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Sensitivity and Specificity <5% ADAMTS13 Activity is very specific for TTP* Sensitivity Furlan 1998 86% Tsai 1998 100% Veyradier 2001 71% Mori 2002 66% Vesely 2003 33% Studt 2003 60% *Controversial
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ADAMTS13 Activity in TTP/HUSRelation to Presenting Features and Clinical Outcomes in a Prospective Cohort of 142 Patients Outcome <9% activity the death rate = 12% >10% activity the death rate = 40% Vesely, Blood 2003; 102(1) 60-68.
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The Future ? Development of monoclonal antibodies for more accurate ADAMTS13 assays Recombinant ADAMTS13 for therapy
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Conclusion Cryopoor plasma therapy appears to be more effective when used initially Splenectomy was effective salvage therapy for > 50% of our refractory patients
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Presentation Infuse FFP one unit/hr until PE PE – 35mL/Kg (one plasma volume)Cryopoor plasma ASA 100mg/day steroids + Immuran Folic acid, 2 mg/day DO NOT TRANSFUSE PLATELETS! McCarthy LJ. Do platelet transfusions to patients with TTP influence their survival? Blood. 1994;84(Suppl 1):669a.
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TTP in Review TTP becoming more common Cause(s) unknown We now have effective treatment Plasma, plasma and more plasma Treat aggressively and immediately TTP is a true emergency No recovery from cardiac arrest
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Principles of Treatment Patients never too sick to make a complete recovery Treat until recovery or death Patients never so well that they cannot die Treat immediately and aggressively Reduce therapy slowly
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"Prediction is very difficult, especially about the future." Niels Bohr
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"Those who cannot remember the past are condemned to repeat it." George Santayana,Reason in Common Sense(New York: Scribner's, 1905)
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