Diagnosis and Treatment of Common TMAs
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1 Diagnosis and Treatment of Common TMAs K. Pavenski, MD FRCPC St. Michael s Hospital June 13, 2014
2 Disclosures I have a relevant conflict of interest - Alexion Pharmaceuticals Inc. Participated in advisory boards Received honoraria for speaking
3 Outline TMA DDx TTP Basics ahus Pathophysiology Diagnosis Management
4 Case 1 26 yo female with recent diagnosis of adult onset Still s disease and central retinal artery occlusion Medications: prednisone 20 mg od, pantoprazole, Ca/Vit D Routine labs at the rheumatologist s office: Hemoglobin 64g/L, platelets 63x 10 9 /L and WBC 6.36x10 9 /L Creatinine 532 umol/l, LD 734 ( u/L) BFR: thrombocytopenia and moderate RBC fragmentation
5 Case 1 P/E: unchanged eye findings; BP 180/100mmHg Confirm hemolysis: LD 734 ( u/L), normal bilirubin and an undetectable haptoglobin Asssess target organ damage Creatinine 532 umol/l, normal lytes; urinalysis: protein >3g, large amount of blood and no casts Troponin normal Alert, no focal deficits Diagnostic work-up Normal coagulation studies Negative beta HCG Negative DAT
6 Case 2 41 yo female with?new diagnosis of mixed connective tissue disease (MCTD), only medication is Naproxyn prn HPI Presented to ER with 1 week history of weakness and bruising Admitted under medicine with ITP and received IV high dose steroids Now somnolent, CT head negative for hemorrhage Labs: Hemoglobin 68g/L, platelets 4x 10 9 /L and WBC 6.8x10 9 /L Creatinine 63 umol/l, LDH 1192U/L ( ) BFR: severe thrombocytopenia and moderate RBC fragmentation
7 Case 2 Confirm hemolysis: LD 1192U/L ( ), total bilirubin 33 (direct 7), haptoglobin undetectable Asssess target organ damage Creatinine 63 umol/l, normal lytes; urinalysis: not done Troponin I 2.29 ug/l (<0.04) Alert, no focal deficits Diagnostic work-up Normal coagulation studies Negative beta HCG Negative DAT
8 TMA: Differential Diagnosis TTP (severe ADAMTS13 deficiency) DIC Congenital (USS) (5%) Acquired (95%) Primary Secondary (infections, autoimmune conditions, pancreatitis, medications) HUS STEC-HUS (90%) ahus (10%) Genetic Anti-Factor H antibody 34% 12% Secondary TMA (normal ADAMTS13) Malignant HTN HELLP Autoimmune disease (scleroderma, APLAS, SLE, etc.) Infections (H1N1, S. pneumonia) Malignancy Drugs of abuse (cocaine) Prescribed drugs (calcineurin inhibitors, gemcitabine, VEGF inhibitors, etc.) Solid organ transplant Bone marrow transplant 54% Data from Fujimura & Matsumoto 2009
9 If this could be TTP, treat now Investigate later Without appropriate treatment, mortality is > 85% Alive With treatment, mortality is < 15% Dead Dead Alive
10 TTP: Diagnostic Criteria Microangiopathic hemolytic anemia anemia, RBC fragmentation on BFR, biochemical evidence of hemolysis Thrombocytopenia Tissue damage (kidney, brain, heart) Other organs may also be involved GI tract Absence of a clear alternative diagnosis Normal coagulation studies
11 TTP: Incidence Standardized annual incidence in adults x 10(6) (95% CI: ) for all patients with clinically suspected TTP-HUS 1.74 x 10(6) (95% CI: ) for patients with severe ADAMTS-13 deficiency (<5% activity) In Canada, about 200 patients with TTP/HUS are treated with plasmapheresis every year (population: 36 million) Terrell et al 2005; CAG data
12 TTP: Pathophysiology Autoimmune disease IgG antibody directed against ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motifs-13) Antibody can be detected by inhibitor studies or ELISA; presence of inhibitor/antibody is consistent with acquired TTP ADAMTS13 Cleaves VWF within the central A2 domain Activity can be measured (ex. Collagen binding assay, ELISA); low activity (<10% is consistent with TTP) Collect sample for ADAMTS13 testing prior to the administration of plasma! Camilleri et al 2012
13 Normal Physiology VWF cleaved by ADAMTS13 ADAMTS-13 platelets vwf multimers Courtesy of A. Tam, MD
14 TTP: Pathogenesis Deficiency of ADAMTS13: congenital or acquired Acquired = autoantibodies vs. ADAMTS13 vwf-plt interaction Platelet activation Activation of secondary hemostasis Microvascular thrombosis Abnormally large vwf multimers Courtesy of A. Tam, MD
15 TTP: Pathogenesis Is ADAMTS13 deficiency sufficient to cause clinical disease? Yes: in a baboon model, functional inhibition of ADAMTS13 triggered a syndrome equivalent to TTP (Feys et al 2010) No: there are patients with low/undetectable ADAMTS13 and no disease (George 2010); in a mouse model, 2 nd hit is required (Banno et al 2006) Could other targets/antibodies be involved? Severe deficiency is detected in only 18-72% of TTP patients (Manucci & Franchini 2012) Association with complement activation and complement consumption that is variable from patient to patient (this has been known since 1970 s; most recent reference is Westwood et al BJH 2014) Requirement for a triggering event? (shear stress, release of ultra large VWF multimers, oxidation of VWF, free hemoglobin) Infection, pregnancy, pancreatitis, autoimmune disease, drugs (clopidogrel), etc.
16 Utility of ADAMTS13 Assays Confirm diagnosis Severe deficiency (<5%) has high specificity for TTP (Scully et a 2012) Predict short-term outcomes (acute mortality, remission) Severe deficiency associated with better outcomes (Vesely et al et al 2003) and possibly response to PLEX Predict relapse Relapse rate greater in those with ADAMTS13 activity < 10% (16 of 47, 34%; estimated risk for relapse at 7.5 years, 41%) than among those with ADAMTS13 activity of 10% or more (5 of 136, 4%; P <.001) (Kremer Hovinga et al 2010) Monitor disease course Controversial - may be useful only if changes from normal to low Determine need for additional treatments For eg. Rituximab for inhibitor eradication
17 Acquired TTP: Treatment Therapeutic Plasma Exchange (TPE) Removes autoantibody, repletes ADAMTS13, removes ultra large VWF multimers, immunomodulates Start as soon as possible (British Guidelines: within 4-8 hrs) Usual TPE prescription: 1.5 PV daily for 3 days then 1.0 PV daily until PLT>150 for at least two consecutive days followed by a taper over two weeks CSP or frozen plasma as replacement fluid SDP if history of or new development of allergic reaction to plasma Plasma infusion is acceptable while awaiting transfer to a TPE centre
18 Acquired TTP: Treatment Steroids Recommended upfront use of methylprednisolone 1g/d for 3 days or prednisone 1mg/kg/d (British Guidelines) ASA Reasonable to use once PLT>50 with aim to prevent thrombotic events Platelet Transfusions Very controversial (Swisher et al 2009) Consensus: avoid unless serious clinical bleeding or undergoing major surgery
19 Acquired TTP: Other Treatments Refractory or relapsed setting Rituximab Used at a lymphoma dose 375mg/m 2 q1wk for 4 wks >90% response rate in refractory patients within 14 days and 13% relapse rate at a median 24 months (Westwood et al, 2013) Splenectomy Vincristine TPE large volume or BID Cyclosporine Cyclophosphamide IVIG Bortezomib
20 Acquired TTP: Outcomes Acute mortality is 10-20% (Scully et al 2012) Long-term complications Life-time risk of relapse 30%, highest in the 1 st 8 years A significant proportion have persistent cognitive abnormalities (Kennedy et al 2009) Increased incidence of HTN, major depression and premature death in patients who have recovered from TTP vs. age/sex/race matched controls (Deford et al 2013)
21 TTP: Resources Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies. Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, Cheung B, Machin SJ; British Committee for Standards in Haematology. Br J Haematol Aug;158(3): How I treat patients with thrombotic thrombocytopenic purpura: George JN. Blood Nov 18;116(20): TTP order sets
22 TTP: Order Sets
23 TTP: Resources for Patients
24 Case 1 The patient is admitted and TPE with CSP is started She is started on antihypertensives and high dose steroids (because of her Hx of AOSD) 24 hrs later she develops generalized tonic clonic seizures followed by decreased LOC Intubated and transferred to ICU Loaded with Dilantin Dialysis initiated for volume overload On steroids, dialysis and plasmapheresis, she improves and eventually is weaned off hemodialysis and plasmapheresis and steroids are tapered
25 Case 1 Laboratory Investigations ADAMTS13 activity 68% by ELISA Negative autoimmune serology lupus anticoagulant or anticardiolipin antibody; negative extractable nuclear antigens, antinuclear antibody, anti double stranded DNA antibody, rheumatoid factor, and antineutrophil cytoplasmic antibody Increase in levels of inflammatory markers ferritin 816 at presentation and peaking at >1500nmol/L; CRP 8.2 ( mg/l). No evidence of infectious disease
26 Case 1 Laboratory Investigations Complement studies (protein), Germany: C ( g/L), C ( g/L) Normal classical pathway function 72% (65-135) and alternative pathway function 123% (60-140), normal C3d 30 (<40U/mL), high SC5b (<320ng/mL), low C ( mg/mL), low normal factor H 298 ( ug/mL) and factor I 23 (21-46ug/mL), and negative anti-h antibody Complement Genetics, Hospital for Sick Children (Toronto) heterozygous for a mutation of unknown significance in the C3 gene (C1685C>T change); not previously reported but predicted to be benign
27 Case 1 10 days after stopping TPE Develops headache, worsening vision, malignant hypertension and an altered level of consciousness/seizure She is intubated and transfered to the ICU Repeat MRI: PRES She is dialyzed, plasmapheresed and eculizumab 900 mg IV is administered
28
29 Case 1 Within days, clinical improvement and hematologic remission Due to difficulties of obtaining further doses of eculizumab and taking into account remarkable progress, no further doses of eculizumab were administered She remains on a low dose of corticosteroid She is dialysis free (Cr 111umol) No recurrence of AOSD
30 Case 2 Patient admitted and started on PLEX ( PV exchange with CSP daily) High dose steroids (1mg/kg/day) continued Work-up ADAMTS13 <0.01U/mL (severe deficiency) ENA 221 (anti-sm-rnp>250) ANA 15.1, C3 0.73, C4 0.12
31 Case 2 Clinical course Post 3 rd exchange, plt 25 Post 7 th exchange, plt 172 PLEX weaned followed by a steroid taper
32 Hemolytic Uremic Syndrome (HUS) 90% is due to STEC-HUS (formerly called diarrheaassociated HUS) 10% is due to uncontrolled activation of the alternative pathway of the complement system Genetic (sporadic or familial) Acquired due to anti-h antibody Usually associated with complete deficiency of Factor H related proteins (CFHR) 1 and 3 Note: cause can be identified in about 70% of cases with appropriate testing Rare causes: methyl-malonic aciduria with homocystinuria, etc.
33 Complement Cascade Meri 2013
34 ahus: Epidemiology Annual incidence USA: 1-2 cases per million (all) European Medicines Agency: 3.3 case per million (<18yo) Slight female preponderance in adults Time of onset more common before 18 yrs (60% of cases) (range: 1 day to 83 yo) Patients with CFI and C3 mutations tend to present in adulthood Loirat & Fremeaux-Bacchi 2011
35 ahus: Diagnostic Criteria There are no established consensus diagnostic criteria Commonly used criteria MAHA Thrombocytopenia Renal dysfunction (acute renal failure, proteinuria, hematuria) Alternative diagnoses excluded (STEC-HUS, TTP, others) Demonstration of a genetic defect is not required for diagnosis in about 50% of patients, no mutation is identified
36 ahus: Mechanism Meri 2013
37 ahus: Genetics Inheritance is autosomal dominant with incomplete penetrance >120 mutations in genes encoding complement regulators CFH, CFI, and MCP (CD46) loss of function Mutations in genes encoding complement proteins CFB and C3 gain of function Not uncommon to have more than one mutation ( double mutants ) Other defects associated with ahus: THBD (thrombomodulin), DGKE (diacylglycerol kinase e)
38 ahus: requirement for a 2 nd hit A triggering event is necessary (and is clearly identifiable in 70% of patients) GI infection and URTI accounts for 50% of cases overall and 80% of pediatric cases Pregnancy 20% of women have onset peripartum with large majority presenting post-partum Worse during 2 nd pregnancy Other triggers: varicella, H1N1, STEC-HUS Noris et al 2010; Loirat & Fremeaux-Bacchi 2011
39 ahus: Clinical Presentation MAHA Thrombocytopenia Renal: acute renal insufficiency/failure, proteinuria, hematuria, oliguria Extra-renal manifestations occur in 10-30% (except MCP mutations who have none) Eyes: visual loss (retinal vein thrombosis) Neurological (48%): confusion, encephalopathy, headache, seizures, focal deficits Cardiac: hypertension, chest pain, SOB, MI (3%), heart failure, cardiomyopathy, cardiac arrest Pulmonary: hemorrhage GI: diarrhea (30%), abdominal pain, nausea/vomitting, pancreatitis Miscellaneous: edema, effusions, anasarca Noris et al 2010 Campistol et al 2013
40 ahus: Laboratory Work-Up Confirm fragmentation hemolytic anemia, thrombocytopenia Assess tissue damage: kidney, heart, brain, etc. R/O alternative diagnosis ADAMTS13 activity in normal range (SMH) Stool culture or Shiga-toxin PCR negative if appropriate Rule out active malignancy, drugs, autoimmune conditions Complement Genetics (Hospital for Sick Children) C3, CD46, CFB, CFH, CFHR5, CFI and THBD Complement levels: C3, C4, CH50 (SMH) Expect low C3 in patients with C3 or CFH defects Expect CH50 to be elevated neither sensitive nor specific Other complement studies (Reference laboratories) CD46 expression (flow) Factor H and Factor I levels, anti-h Antibody not available Biomarkers of complement activation (C3a, C5b-9, etc.) not available C5a and C5b-9 may be particularly useful in differentiating ahus (Cataland et al, 2014)
41 ahus: Clinical Course About 80% of cases have an abrupt onset of disease Acute mortality: 10-15% Chronic condition (?relapsing-remitting) About 50% progress to ESRD 40-70% of patients with CFH, CFI, C3 or THBD mutations or anti- H antibodies develop ESRD or die during the 1 st episode or within 3 years of disease onset Patients with MCP have best prognosis; CFH and THBD have the worst prognosis About 50% have relapses Patients with MCP mutations have highest number of relapses Adults have worse prognosis than children Familial cases had worse prognosis than sporadic cases Noris et al 2010
42 ahus: Treatment with Plasmatherapy PI vs. TPE not clear which one is better; no prospective trials Mechanism replenishes normal complement regulators, eliminates dysfunctional native inhibitors, eliminates pathogenic antibody Treatment protocols vary start ASAP Induction: 1.5PV exchange daily until platelets normalized, hemolysis stopped and renal function improved/stabilized Maintenance: 5 TPE per week for 2 weeks, 3 TPE per week for 2 weeks Usually FP is used as a replacement fluid Noris et al 2010
43 ahus: Treatment with Plasmatherapy Induces complete or partial remission in about 70% of episodes/50% of patients Response is the worst for CFI and CFH mutants (less than 25% of episodes) and best for MCP and THBD mutants Children respond better than adults Complications Volume overload (PI), transfusion reactions
44 ahus: Treatment with Eculizumab Eculizumab Humanized monoclonal antibody that binds C5 and inhibits its activation Treatment schedule (adult) 900 mg IV q1wk for 4 weeks then 1200 mg q2wks Treat indefinitely lower risk patients may eventually be able to come off after a 12 mos of treatment and under close surveillance (expert opinion) For ahus, approved by FDA in 2011 and by Health Canada in 2012
45 ahus: Treatment with Eculizumab 2 weeks prior to commencement of eculizumab, vaccinate with meningococcal conjugated tetravalent vaccine (serotypes A, C, Y and W135) Note: serotype B is not covered by the vaccine and has high prevalence in Canada; MenB vaccine is available in Canada but is recommended only for children consider vaccination against H. influenza and pneumococci If treatment must start urgently, consider antibiotic prophylaxis with penicillin or amoxicillin until immune Campistol et al 2013
46 Figure 3 Diagnostic algorithm and therapeutic options for ahus Zuber, J. et al. (2012) Use of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies Nat. Rev. Nephrol. doi: /nrneph
47 ahus: Resources for Patients
48 Questions ahus Our knowledge is rapidly growing and changing Consensus diagnostic criteria are necessary for research and practice TTP ADAMTS13 may not be the entire explanation for the pathogenesis of TTP TPE remains the most important treatment strategy Immunosuppression emerges as an important therapeutic adjunct
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