When a patient presents with TMA, identify the underlying cause for the appropriate diagnosis... IS IT TTP OR IS IT ahus?

Transcription

1 When a patient presents with TMA, identify the underlying cause for the appropriate diagnosis... IS IT TTP OR IS IT ahus?

2 ADAMTS13 activity >5% RULES OUT a diagnosis of severe ADAMTS13 deficiency (TTP) 1-7 Genetic, complement-mediated TMA (ahus) ahus is caused by chronic, uncontrolled complement activation 8-15 C3 C5 Permanent genetic mutations in complement regulators Chronic, uncontrolled complement activation Genetic defects in activators and/or inhibitors lead to chronic activation of the complement system, causing endothelial cell damage and continuous platelet aggregation 8-15 C5a C5b-9 Severe ADAMTS13 deficiency (TTP) The underlying cause in TTP is a severe deficiency in ADAMTS13 activity ( 5%) 1-4 Normal ADAMTS13 activity ADAMTS13 deficiency Insufficient ADAMTS13 activity ( 5%) leaves von Willebrand factor (vwf) uncleaved, causing excessive platelet aggregation 1,4,15,16 vwf cleaved vwf uncleaved Identifying ahus as the underlying cause of TMA is critical to effective management decisions 4,6,15,17,18

3 Serum creatinine levels (SCr) and platelet count can be used to predict ADAMTS13 activity in patients with TMA 17,19-23 In a national registry of 214 TMA patients, baseline SCr and platelet count were identified as independently predictive values of ADAMTS13 deficiency* 19 Patient characteristics Adjusted Odds Ratio 95% CI P value Creatinine level 200 µmol/l (2.3 mg/dl) <0.001 Platelet count 30 x 10 9 /L <0.001 A patient with a TMA presenting with SCr >1.7 mg/dl OR platelet count >30,000/mm 3 is 21.8x less likely to have severe ADAMTS13 deficiency (TTP) than those who meet neither criteria 19,24 Multiple studies on a total of 806 patients with TMA have demonstrated that baseline values of SCr and platelets at clinical presentation can rapidly and efficiently distinguish between sufficient and severely deficient ADAMTS13 activity 17,19-23 Serum creatinine level and platelet count show statistical significance in predicting ADAMTS13 activity 17,19-23 Association with severe ADAMTS13 deficiency: P value Authors Serum creatinine level Platelet count Bentley (N=110) P= P= Cataland (N=54) P< P< Coppo 2010* 19 (N=214) P< P< Kremer Hovinga (N=261) P<0.001 P<0.001 Shah (N=60) P= P= George (N=107) P<0.001 P<0.001 ADAMTS13 deficiency defined as ADAMTS13 activity: *<5% (mild deficiency = 5%-20%), <10%, <15%; <10%. ADAMTS13 assays generally have a sensitivity of 5%-10%. 1 Severely deficient ADAMTS13 activity is typically defined as <5%. 1,19

4 Plasma exchange or plasma infusion (PE/PI) as treatment for ahus has been clinically ineffective 8,18,25,26 Complement dysregulation and TMA persist in patients with ahus on PE/PI, even if there is a transient impact on platelet count and LDH levels 27,28 PE/PI is not sufficient to remove mutant complement factors or replace deficient factors Apheresis procedures themselves may also lead to complement activation 31 Mean plasma levels of complement Ba,* a key marker of alternate complement pathway activity, are similarly elevated among ahus patients receiving or not receiving plasma exchange or plasma infusion 28 *Complement component, Ba, is formed upon activation of the alternative complement pathway and cleavage of Factor B. PE/PI does not reduce morbidity in ahus (N=99) P=0.98 % of patients requiring dialysis at 1 year % 33 % 5 0 Received PE/PI No PE/PI Study description: Analysis of patients from the ahus registry of the GPN (Working Group for Pediatric Nephrology). 141 patients were included in the registry at the time of this analysis. Data on treatment of initial manifestations was available for 99 patients. 42% of patients received PE, 48% received PI, and 22 patients received both PE and PI. 32 Patients receiving initial PE/PI have equally poor outcomes after 1 year compared to patients without initial PE/PI 32 According to the American Society for Apheresis, plasma exchange in ahus receives: Weak recommendation, low-quality or very low-quality evidence. 33 This recommendation excludes ahus caused by MCP mutation.

5 ahus is a disease associated with chronic risk of complement-mediated thrombotic microangiopathy (TMA) and life-threatening consequences 25,27,34,35 79% of patients die, require dialysis, or have permanent renal damage within 3 years 8 Cumulative fraction of patients free of events Significant morbidities and mortality within 1 year despite PE/PI* 26 Study description: An analysis of the outcomes of 40 patients with the complement factor H (CFH) mutation from the database of the International Registry of Recurrent and Familial HUS/TTP. The cumulative fraction of patients free of events (defined as the combination of the occurrence of chronic renal insufficiency or initiation of dialysis or death, whichever occurred first after the onset of HUS) was estimated by Kaplan-Meier analysis. * Patients with CFH mutations. CFH mutations = most common population % of these patients received plasma exchange or plasma infusion (PE/PI) Follow-up after initial onset (months) Modified from Caprioli et al, % to 40% of all patients die or progress to end-stage renal disease with the first clinical manifestation despite plasma exchange or plasma infusion (PE/PI) 8,26 Patients diagnosed with ahus are at immediate and ongoing risk of progressive clinical deterioration despite intensive use of PE/PI 8,26

6 Differential diagnosis for TMAs: ahus, TTP, and STEC-HUS Thrombocytopenia 24,26 Platelet Count <150,000/mm 3 24,26 or >25% Decrease From Baseline 24 AND Plus one or more of the following: Microangiopathic Hemolysis 9,26 Schistocytes 9,26 and/or Elevated LDH 26 and/or Decreased Haptoglobin 26 and/or Decreased Hemoglobin 26 Neurological Symptoms Confusion 37,40 and/or Seizures 36,38,40 and/or Other Cerebral Abnormalities 37,39 Renal Impairment 26,35,41-44 Elevated Creatinine 35,41 and/or Decreased egfr 44 and/or Elevated Blood Pressure 42 and/or Abnormal Urinalysis 41 Gastrointestinal Symptoms 8,26,38,45 Diarrhea +/- Blood 40,45 and/or Nausea/Vomiting 38 and/or Abdominal Pain 38 and/or Gastroenteritis 26 Evaluate ADAMTS13 Activity and Shiga-toxin/EHEC* Test 1-4,46 In the absence of ADAMTS13 results, a serum creatinine level > μmol/l (> mg/dl) or a platelet count of >30,000/mm 3 almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP) 19,47 5% ADAMTS13 Activity 1-4 >5% ADAMTS13 Activity 1-4 Shiga-toxin/EHEC Positive 46 TTP ahus Genetic mutations are not identified in 30% to 50% of patients with ahus. A diagnosis of ahus does not require identification of a mutation 48,49 STEC-HUS* TMA = thrombotic microangiopathy. ahus = atypical hemolytic uremic syndrome. TTP = thrombotic thrombocytopenic purpura. STEC-HUS = Shiga-toxin producing E coli hemolytic uremic syndrome. LDH = lactate dehydrogenase. egfr = estimated glomerular filtration rate. EHEC = enterohemorrhagic E coli. * Shiga-toxin/EHEC test is warranted in history/presence of GI symptoms. The information on this page is intended as educational information for healthcare providers. It does not replace a healthcare professional s judgment or clinical diagnosis. References: 1.Tsai H-M. Int J Hematol. 2010;91: Bianchi V, Robles R, Alberio L, et al. Blood. 2002;100: Barbot J, Costa E, Guerra M, et al. Br J Haematol. 2001;113: Sadler JE. Blood. 2008;112: Zheng XL. Blood. 2010;115: Sadler JE, Moake JL, Miyata T, et al. 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