FP328SECONDARY THROMBOTIC MICROANGIOPATHY: DO WE HAVE PROSPECTS FOR THERAPY?

Abstract

INTRODUCTION: The prognosis in patients with secondary thrombotic microangiopathy (TMA) is variable and often poor due to inconsistent treatment. In last years efficiency of Defibrotide (DFT) was demonstrated in TMA associated with hematopoietic stem cell transplantation (HSCT). DFT is likely acts due to endothelial cells protection,thrombotic-fibrinolytic homeostasis restoration. METHODS: We present observations of patients with secondary TMA who received combined therapy, including DFT, and who had a relatively favorable clinical outcome. RESULTS: Patient 1. A 9-mo boy became hypertensive, thrombocytopenic (PLT 85/ ml) and proteinuric (5g/l) on day 21 of the anti-tumor therapy. A few days latter he developed TMA with renal and respiratory fuilure: anemia (HB 70g/l), thrombocytopenia (35/μl-2/μl), schistocytosis (11%,N<2%), decreased haptoglobin (0,1mg/l,N=0,3-2 mg/l), increased LDH activity (800 IU/l;N<250), creatinine 122mmol/l, cystatine C 3mg/l, eGFR=33ml/min/1,73m2. ADAMTS13 levels was 42%, blood C3, C4 was normal. Infectious and autoimmune screening was negative. Druginduced TMA was diagnosed (morphologically confirmed). Renal replacement therapy (7 days), defibrotide 30 mg/kg/day (10 days), fresh frozen plasma 10 ml/kg/day (5 days), symptomatic treatment were started. On day 3 of the therapy platelet count increased (200/μl), hemoglobin stabilized (100 g/l); blood pressure normalizedon day 11. The proteinuria disappeared from 2mo; eGFR is stabile (70 ml/min/1,73m2). Patient 2. A 2 y.o girl with allogeneic HSCT (TCR ab/CD19 depletion) because acute myeloblastic leukemia presented with edema, blood hypertension, respiratory and renal failure (eGFR=49 ml/min/1,73m2), Coombs negative hemolytic anemia (HB 70g/l; PLT 50/μl; schistocytes 8%; haptoglobin 0,08 mg/l; LDH 950 IU/l), proteinuria (5 g/l) associated with Acyclovir/Gancyclovir resistant generalized CMV-infection. Treatment with Prednison 30 mg/kgNo5, Defibrotide 20 mg/kg, Foscavire, Cymevene, CD45 RA(-) transfusion and symptomatic therapy were started. On day 5 of therapy the reconstitution of platelet and hemoglobin, decreasing of serum creatinine level were observed. Blood pressure and creatinine/eGFR normalized from 1 year; the patient still has proteinuria (40 mg/m2). Patient 3. A 9 y.o boy with myelodysplastic syndrome presented with drowsiness, upper extremity tremor, jaw muscle contraction, blood hypertension and proteinuria from 2mo after HSCT. The Tacrolinus neurotoxicity was suspected (CoTac=12 ng/ ml). The withdrawal of drug didn't lead to improvement. The boy developed edema, oliguria; laboratory signs of TMA with renal failure appeared: HB 78g/l; PLT 54/μl; schistocytes 3%; haptoglobin 0,05 μg/l; LDH 750 IU/l, creatinine 390-470 mmol/l, eGFR=15-12 ml/min/1,73m2, proteinuria 5 g/l. Renal replacement therapy (7days), Defibrotide 20 mg/kg (5days) and symptomatic treatment were started with reconstitution of platelet and hemoglobin level. The treatment with DFT was stopped because of renal subcapsular hematomas' occurrence. Blood pressure normalized and proteinuria disappeared from 3mo; the eGFR is 58 ml/min/1,73m2. CONCLUSIONS: The data demonstrate that the blood hypertension and the heavy proteinuria were the first signs of TMA in our patient. We assume that a relatively rapid reversal of TMA symptoms in our patients may be due to combination therapy including DFT. An uncommon side effect of the DFT, renal subcapsular hematomas, was observed.