Initial management of TMA syndromes Elie Azoulay, Saint-Louis Hospital, Medical Intensive Care Unit Paris Diderot Sorbonne University Groupe de Recherche Respiratoire en Réanimation Onco-Hématologique (GRRR-OH)
H E M O L Y S I S T M A S C H I S T O C Y T E S Eculizumab T H R O M B O C Y T O P E N I A O U T C O M E S Drug-Transplantation Cancer Infection C3 B factor C5 Neurological Hypertension TTP H Factor CD46 (MCP) I Factor Unresponsive Multiple Organ Failure Auto-immunity ADAMTS 13 Pregnancy AKI STEC Sudden death Hemorrhage Complement Coma Medical emergency First line therapy Rituximab Steroids? H U S Renal Ischemia ahus Stroke Thrombosis Genetic ICU Second line therapy Renal replacement therapy Idiopathic Differential diagnoses Evans, B12 deficiency, sepsis, HIT COOMBS TEST Plasma exchange Troponin Seizures C A R D I A C Elie Azoulay, Do-Not-replicate
TMA?
Understanding TMAs
Thrombotic microangiopathies Normal erythrocytes Mechanical (non-immune) haemolysis Microvascular thrombosis Aggregation of platelets Ischaemia
TMA diagnosis: basics 1. Mechanical (nonimmune) injury to normal erythrocytes Fremeaux-Bacchi V, et al. Clin J Am Soc Nephrol 2013;8:554-61 George JN, et al. N Engl J Med 2014;371:654 66 Scully M, et al. Br J Haematol 2014;164:759 66 2. Consumption (Peripheral ) thrombocytopenia 3. Microvascular occlusive disorders by platelet aggregation TTP, ischaemia in the brain, heart, etc and most organs HUS, platelet fibrin thrombi occlude predominantly, but not only, the renal circulation
TMA= a Multiple Organ Dysfunction Severe Reversible Confusion Seizures Stroke Encephalopathy Diffuse cerebral dysfunction Elevated creatinine Edema Malignant hypertension Renal failure Dialysis Transplant Prognostic factors hardly apply Hemolysis Decreased platelets Fatigue Transfusions TMA Myocardial infarction Thromboembolism Cardiomyopathy Diffuse vasculopathy Duration of life support Impact of early appropriate management Liver necrosis Pancreatitis Diabetes Mellitus Colitis Diarrhea Nausea/vomiting Abdominal pain
TMA Differential diagnoses ADAMTS13, Complement PEX 60ml/kg/d Corticosteroids 1mg/kg/day BP control Platelet count Creatinine TTP ADAMTS 13 HUS
TTP, atypical HUS and STEC-HUS Noris M, et al. N Engl J Med 2009;361:1676 87 Tsai H, et al. Am J Med 2013;126:200 9 Orth D, et al. J Immunol 2009;182:6394 400 Johnson S, et al. Immunobiology 2012;217:235 43
Mannucci PM. Intensive Care Med 2015 [Epub ahead of print]
Mesenteric ischaemia No platelet transfusion Varia - AKI - Alveolar haemorrhage Thrombosis > Haemorrhage Stroke Hospital acquired infection Myocardial Infarction Peigne V, et al. Intensive Care Med 2012;38:1810 7
a 77-yo Japanese man diagnosed with TTP. The patient suddenly died. On autopsy, myocardial infarction manifested as petechiae and fibrotic foci. The microthrombi in the small arterioles and capillaries were platelet thrombi, which showed positive results for periodic acid-schiff stain and factor VIII on immunohistochemical staining.
The thrombus stains purple-red with the periodic acid Schiff stain = Platelet thrombi The thrombus shows positive results for immunohistochemical staining for factor VIII
2001-2010 Nationwide Inpatient Sample database 4032 TTP patients Mortality 11% Independent predictors of acute myocardial infarction were older age (OR 1.03 (1.02-1.04), smoking (OR 1.60 (1.14-2.24), known coronary artery disease (OR 2.59 (1.76-3.81), and congestive heart failure (OR 2.40 (1.71-3.37). Independent predictors of hospital mortality were older age (OR 1.03 (1.02-1.04), acute myocardial infarction (OR 1.89 (1.24-2.88), acute renal failure (OR 2.75 (2.11-3.58), congestive heart failure (OR 1.66 (1.17-2.34), acute cerebrovascular disease (OR 2.68 (1.87-3.85), cancer (OR 2.49 (1.83-3.40), and sepsis (OR 2.59 (1.88-3.59).
Anti-ADAMTS13 IgG (%) Anti-ADAMTS13 IgG antibodies and Troponin T levels during acute TTP Cases with higher Troponin T levels (>0.1 µg/l) had higher IgG level at presentation (p=0.03) 200 175 Median IgG: 35% Median IgG: 45% Median IgG: 69.5% 150 125 100 75 50 25 0 <0. 01 n=13 0. 01-0. 09 n=11 >0. 1 n=14 Troponin T (µg/l) Scully M et al. J Thromb Haemost 2009
Takotsubo cardiomyopathy Ventriculogram Two-chamber view of the left ventricle, obtained in diastole (A) and systole (B). Panel B demonstrates the akinetic and balloon apex in systole with a hypercontractile base.
Management of TTP Admission to an ICU/HDU (intense needs, lines, PEX). Urgent (within 4-8h) PEX 60ml/kg: ADAMTS13 sup + AB removal, daily and until 2 days after platelet count normalizes. 100% plasma. Corticosteroids 1mg/kg/day (high doses for 3 days?) Low-dose aspirin, DVT prophylaxis, central venous access without platelet transfusion, and Folic acid. Rituximab is safe and effective for newly diagnosed TTP: decrease the number of PEX. Early?
Plasma 40-60 ml/kg (1-1,5 blood mass) Within 6h of admission Massive transfusion of functionnal ADAMTS13 Clear anti-adamts13 antibody Clear UL Wb factor
Rock et al. The Canadian Apheresis Group 103 pts, 7 y, 18 centers PEX vs. Plasma transfusion Survival 1,8,6,4 G1: Plasma exchange G2: Plasma infusion Group 1: 15.8 EP (3 à 36), 21.5+7.8 liters PVI Group 2: 7.7 jours de PVI. 6.7+3.3 liters PVI,2 0 P=0,03 0 5 10 15 20 25 30 35 Weeks N Engl J Med. 1991 Aug 8;325(6):393-7.
Darmon M, et al. Crit Care Med 2006;34:2127 33
Management of unresponsive TTP Unresponsive to PEX + steroids Check everything, avoid differential diagnoses Rituximab High dose steroids Vincristine, other IS agents (cyclophosphamide etc ) Splenectomy: late line option
OR 95% CI P value Age >60y 7.90 1.06-78.34 0.04 Neurological symptoms - Headaches - Severe symptoms 8.04 1.71 1.27-51.03 0.42-7.09 0.02 0.45 Cardiac signs at presentation 3.44 1.63-16.39 <0.01 Platelet rate at day 2<15 G/L 3.88 1.30-11.62 0.01 Mariotte E, et al. Intensive Care Med 2013;39:1272 81
HUS: Mesangiolysis, fibrin thrombi and fibrinoid necrosis involving the glomerular vascular pole Arteriolar & capillary microthrombi (white clots, platelet-rich fibrin-poor) Fibrin thrombi Fibrinoid necrosis Mesangiolysis El Husseini et al. Am J Kidney Dis. 65(1):127-130
Chronic uncontrolled complement activation leads to systemic TMA in ahus Chronic uncontrolled complement activation Platelet Platelets: activation aggregation Leukocytes: activation Endothelial cells: activation swelling and disruption Red cells: complement deposits haemolysis Endothelial swelling and disruption Platelet aggregation Clinical consequences: Platelet consumption Mechanical haemolysis Blood clot formation Vessel occlusion Inflammation Ischaemia Hypoxia Systemic multi-organ complications Meri S, et al. Eur J Int Med 2013;24:496 502; Zipfel PF, et al. Curr Opin Nephrol Hypertens 2009;19:372 8 Desch K, et al. JASN 2007;18:2457 60; Licht C, et al Blood 2009;114:4538 45 Noris M, et al. N Engl J Med 2009;361:1676 87; Ståhl A, et al. Blood 2008;111:5307 15 Morigi M, et al. J Immunol 2011;187:172 80
ahus confirmed clinically ADAMTS13>10% (result within 24 hours) Samples for complement (serum & EDTA) DO NOT WAIT FOR RESULTS Complement analysis does not support diagnosis of ahus, Diagnosis of ahus does not require identification of a genetic mutation Vaccinations: tetravalent meningococcal and Bexsero (meningococcal B) Antibiotics: penicillin based Eculizumab: 900 mg x 4 weeks 1200 mg every 2 weeks Monitor effect : CH50/CH100 Eculizumab Summary of Product Characteristics. Alexion Europe SAS, 2014 Legendre CM et al. N Engl J Med 2013;368:2169 81
5-7% 1-4% 4-8% 23-27% 2-8% 3% X Eculizumab (SOLIRIS )
37 patients (2 cohorts) with PEX observation followed by Eculizumab
Earlier intervention with eculizumab in patients with ahus leads to greater improvement in egfr Combined dataset C08 and C10 egfr, estimated glomerular filtration rate Vande Walle J et al. J Nephrol 2015;30:127 134
Open-label single-arm phase 2 trial. Multicenter multinational study of ahus patients. 41 patients were treated with IV eculizumab for 26 weeks. 30 (73%) had complete TMA response. All 35 patients on baseline plasma exchange/plasmainfusion discontinued by week 26. Of 24 patients requiring baseline dialysis, 5 recovered kidney function before eculizumab initiation and 15 of the remaining 19 (79%) discontinued dialysis during eculizumab treatment. Two patients developed meningococcal infections
Evolution of egfr under eculizumab treatment in adults with ahus 29.3 ml/min/1.73m 2 : mean change from baseline in egfr at Week 26 Dialysis could be discontinued 20/24 (83%) of patients on dialysis at baseline could discontinue dialysis 15/17 (88%) patients not on dialysis at baseline, remained dialysis-free through the study evaluation period
Key points: TMA and the intensivists 1. Diagnostic challenges exist even for seniors/specialists. 2. Delayed diagnosis and treatment impacts on survival 3. Sudden deterioration. 4. Access to resuscitation facilities. 5. Adjuvant/novel therapies may be required. 6. Lack of awareness of intervention required to differentially diagnose TMA cause 7. Organ involvement = severe and poor prognosis. 8. Treatment should not be delayed. 9. Specialist-led, multi-specialty input achieves high-quality care 10. There is the need for both acute and long-term care for a condition that carries a significant risk of relapse. Dutt T, et al. BJH 2015;170:737 42
Thank you for your attention