OVERVIEW OF TMA AND DIFFERENTIAL DIAGNOSIS

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1 OVERVIEW OF TMA AND DIFFERENTIAL DIAGNOSIS P.M. Mannucci IRCCS Ca Granda Maggiore Policlinico Hospital Foundation and University of Milan

2 THROMBOTIC MICROANGIOPATHIES (TMAs) Definition Characterized by disseminated and massive thrombus formation and endothelial damage in the microcirculation Consequent peripheral thrombocytopenia, mechanical (microangiopathic) hemolytic anemia and multiorgan ischemic dysfunction High morbidity and mortality

3 THROMBOTIC MICROANGIOPATHIES (TMAs) TTP HUS Acquired Typical (STEC-HUS) Congenital Atypical (ahus) 4 cases/million/year 2 4 cases/million/year Other TMAs DIC HELLP syndrome Catastrophic antiphospholipid syndrome (CAPS) Malignant hypertension Cancer Transplantation HIV

4 OUTLINE OF THE PRESENTATION 1. Pathophysiology of thrombotic thrombocytopenic purpura (TTP) 2. Pathophysiology of atypical HUS (ahus) 3. Why an accurate differential diagnosis is warranted

5 TTP: A MULTIORGAN DISEASE DUE TO INTRAVASCULAR PLATELET AGGREGATION: NOT ONLY IN THE CENTRAL NERVOUS SYSTEM! Myocardium Pancreas Kidney Adrenal glands

6 ROLE IN TTP OF VON WILLEBRAND FACTOR (VWF) AND THE SEVERE PLASMATIC DEFICIENCY OF THE VWF-CLEAVING PROTEASE ADAMTS13 Unusually large VWF multimers vwf multimers Lower molecular weight multimers 500 kda NHP TTP Unusually large multimers ADAMTS13 plasma levels in TTP: less than 5-10% Platelet aggregation Thrombi

7 UNMEASURABLE ADAMTS13 LEVELS IN TTP, BUT NOT IN HUS AND OTHER TMAS Hassan et al. Br J Haematol 2015;171: 830-5

8 MEASUREMENT OF ADAMTS13 ACTIVITY Plasma levels of ADAMTS13 can be accurately measured, but not in all clinical laboratories, particularly in emergency Interest in simpler laboratory tools to predict in emergency severe ADAMTS13 deficiency (activity <5-10%) and thus to diagnose TTP

9 OUTLINE OF THE PRESENTATION 1. Pathophysiology of TTP 2. Pathophysiology of atypical HUS (ahus) 3. Differential diagnosis between TTP and ahus

10 PATHOPHYSIOLOGY OF ATYPICAL HUS (ahus, also called complement-mediated HUS )

11 SIMPLIFIED SCHEME OF THE COMPLEMENT SYSTEM Classical and lectin pathways C3 convertase (C4b2a) C3 C3b Alternative pathway C3 convertase (C3bBb) MAC C5-9 (formation) C5 (activation) C3b (C5-convertase) Cellular membrane Noris M & Remuzzi G. N Engl J Med 2009; 361: MAC: Membrane Attack Complex C5a: Anaphylatoxin

12 THE TWO HIT MODEL OF ahus Nester et al. Molecular Immunology 67 (2015) 31 42

13 COMPLEMENT ACTIVATING CONDITIONS CAN TRIGGER ahus Heightened complement activation Abnormal complement proteins Endothelial damage platelet activation thrombin generation ahus Laurence J. Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical Hemolytic Uremic Syndrome (ahus) Essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol 2016; 14(11) Suppl. 11) 13

14 GENETIC LOSS-OF-FUNCTION OF NATURAL COMPLEMENT INHIBITORS OR GAIN-OF-FUNCTION OF COMPLEMENT FACTORS MAY LEAD TO UNCONTROLLED ACTIVATION OF THE ALTERNATIVE PATHWAY Classical and lectin pathways C3 convertase (C4b2a) Mutations in ahus C3 C3b Alternative pathway C3 convertase (C3bBb) MAC C5-9 (formation) C5 (activation) C3b (C5-convertase) Factor H MCP Mutations Factor I in ahus thrombomodulin Cellular membrane Noris M & Remuzzi G. N Engl J Med 2009; 361: MAC: Membrane Attack Complex C5a: Anaphylatoxin

15 FREQUENCY OF LOSS-OF-FUNCTION AND GAIN-OF-FUNCTION MUTATIONS IN GENES ENCODING COMPLEMENT PROTEINS IN ahus Mutated gene Frequency reported (%) Factor H Factor I 4-10 C Thrombomodulin 5 Membrane cofacor protein (MCP) No genetic mutation identified in ca. 50% of patients with atypical HUS Poor diagnostic value of genetic testing Noris M, et al. Clin J Am Soc Nephrol 2010; 5: ; Fremeaux-Bacchi V, et al. Clin J Am Soc Nephrol 2013: 8:

16 WHY A DIFFERENTIAL DIAGNOSIS BETWEEN TP AND ahus IS WARRANTED The past as prologue: plasma therapy was the only and common weapon Recent therapeutic advances in ahus (eculizumab) changed the scenary

17 PLASMA THERAPY Plasma infusion Plasma exchange Circulating disease-causing factors can be removed by exchange and missing plasma factors can be replaced by the infusion of normal plasma. Plasma therapy is still the only therapy with near complete global availability and therefore it remains an important treatment, definitely for TTP but also for ahus, despite poor long-term renal outcome.

18 ATYPICAL HEMOLYTIC UREMIC SYNDROME: GLOOMY OUTCOMES DESPITE PLASMA THERAPY! Case-fatality rate: 10 to 20% Rate of progression to end-stage renal disease: 50% Noris et al. Cl J Am Soc Nephr 2010;5:1844

19 Terminal Proximal ECULIZUMAB BLOCKS TERMINAL COMPLEMENT Hypersimplified complement cascade Eculizumab C3 C3b C3a Eculizumab: a humanized murine monoclonal antibody binds with high affinity to C5 Terminal complement C5a and C5b-9 formation blocked C5 C5b C5a C5b-9 Proximal functions of complement remain intact Weak anaphylatoxin Immune complex clearance Microbial opsonisation Please see full prescribing information for eculizumab. 1. Eculizumab Summary of Product Characteristics. Alexion Europe SAS, 2012; 2. Rother RP et al. Nat Biotechnol 2007;25: ; 3. Walport MJ. N Engl J Med 2001;344: ; 4. Figueroa JE, Densen P. Clin Microbiol Rev 1991;4:359-95

20 THERAPY WITH ECULIZUMAB Dramatic clinical improvements following its administration to ahus patients The key of its therapeutic adoption is the differentiation of ahus from TTP

21 Differential diagnosis of TTP/aHUS

22 ASPECTS OF DIFFERENTIAL DIAGNOSIS Clinical evaluation Shiga-toxin tests for diarrhea-associated HUS Complement serum markers No reliance on prevalent organ symptoms (48% of ahus cases have CNS symptoms, 20% of ahus cases present with initially normal creatinine) PCR Coli positivity on stool samples distinguishes STEC HUS from ahus (and from TTP and other TMAs) Normal in many patients with ahus

23 POOR DIAGNOSTIC VALUE OF COMPLEMENT ACTIVATION SERUM MARKERS IN PATIENTS WITH ACUTE ahus Marker % abnormal Reduced C3 serum levels 18% Increased C5a levels* 19% Increased C5b-9 levels ** 19% Reduced Factor H 16% * Anaphylatoxin ** Membrane attack complex Noris M et al. Blood 2014; 124:

24 THE MAIN WEAPON FOR DIFFERENTIAL DIAGNOSIS ADAMTS13 plasma Levels below 5-10% measurement diagnose TTP and differentiate it from ahus, the latter presenting with measurable plasma levels

25 ADAMTS13 LEVELS IN TTP, HUS AND OTHER TMAs Hassan et al. Br J Haematol 2015;171: 830-5

26 OTHER ASPECTS OF DIFFERENTIAL DIAGNOSIS Two simple laboratory tests may help to predict severe ADAMTS13 deficiency: serum creatinine and platelet count

27 SIMPLE PREDICTION OF SEVERE A13 DEFICIENCY Patient characteristics Adjusted odds ratio (OR) 95% CI Creatinine <200 µmol/l (<2.26 mg/l) , 62.5 Platelets <30 x 10 9 /L , 24.8 Prediction of severe ADAMTS13 deficiency Sensitivity: 98.1% Specificity: 48.1% Positive predictive value: 85% Negative predictive value: 93.3% Coppo P et al. Medicine (Baltimore) 2004;83: Coppo P et al. PLoS One 2010;5:e10208

28 SIMPLE PREDICTION OF SEVERE A13 DEFICIENCY: A RECENT ENDORSEMENT Mild or moderate thrombocytopenia and/or severe kidney injury suggest that the diagnosis is not TTP Page et al. Blood Advances 2017; 1:590

29 TMA DIFFERENTIAL DIAGNOSIS: ahus, TTP, and STEC-HUS 1 Measure ADAMTS13 activity and, if diarrhoea is present, Shiga-toxin culture and PCR 1 While ADAMTS13 results are awaited, a platelet count >30,000 mm 3 or serum creatinine >2.3 mg/dl "almost eliminates" a diagnosis of severe ADAMTS13 deficiency (i.e., TTP) 2 and suggests by exclusion a diagnosis of ahus <5-10% ADAMTS13 activity >5-10% ADAMTS13 activity Shiga toxin positive TTP ahus STEC-HUS 1. Laurence J. Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical Hemolytic Uremic Syndrome (ahus) Essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol 2016; 14(11) (Suppl. 11) 2. Zuber J et al. Nat. Rev. Nephrol. 2012; 8(11):

30 ATYPICAL HUS: not only a diagnosis of exclusion?

31 ATYPICAL HUS MAY BECOME A DIAGNOSIS OF INCLUSION Ham test for PNH Indirect Ham test for ahus Gavriilaki et al. Blood 2015;125:

32 For more details.

33 TAKE HOME MESSAGE ahus is a chronic, progressive disease, often resulting from the uncontrolled activation of the alternative complement pathway The clinical manifestations of ahus lead to significant morbidity and premature mortality Plasma exchange/plasma infusion has limited clinical effectiveness in ahus, but complement blockage by eculizumab is very effective in ahus Laurence J. Haller H, Mannucci PM, Nangaku M, Praga M, Rodriguez de Cordoba S. Atypical Hemolytic Uremic Syndrome (ahus) Essential aspects of an accurate diagnosis. Clin Adv Hematol Oncol 2016; 14(11) Suppl. 11)

34 TAKE HOME MESSAGE 1. It is mandatory to distinguish ahus from TTP in the era of targeted therapies (i.e. complement blockade for ahus; for TTP, rituximab, ADAMTS13 replacement products, inhibitors of von Willebrand factor/platelet reactions such as aptamers and the nanobody caplacizumab) 2. Meaurement of ADAMTS13 activity is the most reliable tool to distinguish TTP from ahus 3. Simpler measurements, such as a very low platelet count, contrasting with normal or low borderline serum creatinine, help to predict severe ADAMTS13 deficiency (<5-10%) and thus to tentatively exclude in emergency situations ahus (characterized by higher platelet count and more severe renal dysfunction) 4. New emerging laboratory tests may help to diagnose ahus more specifically and tailor eculizumab dosing, but they need greater clinical validation

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