1、Thrombotic MicroangiopathyGong MengchunPeking Union Medical CollegeNov 2013Key PointsDefinitionClassificationPathophysiologyClinical MenifestationDiagnosisTreatmentDefinition TMAMicrovascular occlusive disorders characterized bySystemic or intrarenal aggregation of platelets ThrombocytopeniaMechanic

2、al injury to erythrocyteMoschcowitz 1924: TTPGasser 1955: HUSClassificationType of MicroangiopathyCauseClinical PresentationSystemic platelet thrombiFailure to degrade the large multimers of vWFThrombocytopenia Thrombotic Purpura(TTP)Predominantly Renal platelet-fibrin thrombiExposure of Shiga toxin

3、Classic, Childhood HUS (E.coli associated)Defect in plasma factor HFamilial HUSRenal or Systemic thrombiTransplantation or drugs (mitomycin, cyclosporine, tacrolimus, quinine)HUS or TTPPathophysiology: TTPPathophysiology: TTPDefectClinical PresentationADAM TS13 plasma activity 5% of nl Gene mutation

4、Familial TTP Autoantibodies against ADAM TS13Acquired idiopathic TTP Transient defect in production or survival of ADAM TS 13Acquired idiopathic TTPNormal plasma ADAM TS 13 activity with defective attachment of ADAM TS13 to endothelial cellsFamilial or acquired TTPPathophysiology: acquired HUSAcquir

5、ed HUS: Shiga Toxin released by E.coli O157:H7Familial HUS: Plasma H factor deficiencyoveractivation of C3 pathwayPathology: TTPClinical MenifestationsPentad of TTPMicroangiopathic hemolytic anemiaThrombocytopeniaNeurologic disordersRenal disordersFeverMAY DELAY THE TREATMENT!New StrategyAn RCT demo

6、nstrated criteria for TTP:MAHAThrombocytopenia (2 / HPF (100)Polychromatophilic red cells (reticulocytosis)LDH UCB Coombs test (-)What others?TTPHUSMechanismsAbnl ADAM TS13 activity Shiga toxin/ H factor deficiencyPopulation Adults (acquired); Children (familial)ChildrenProdromeBloody diarrheaInvolv

7、ed organCNS and any other (kidney, lung, heart)Kidney and extrarenal organsTreatmentPlasma Exchange, Cryosupernatant, FFP, GCS, Immunosuppressvie agents, SplenectomyMainly supportivePrognosis90% survival if plasma exchange is initiated in time. 90% can be cured solely by supportive treatment; pruden

8、t Abx.Management ProcessPLT + MAHA+ no other causes TTPIf Children+ renal + diarrhea HUS supportiveInitiate Plasma exchange ASAP. + GCS if idiopathicLook for other causes: sepsis, tumor? yes stop PEContinue Rx till remissionRemission not achieved+ other immunosuppressive agents /+ Plasma exchange in

9、tensityTherapy: TTP1. Plasma exchange Clearance of antibodies to ADAM TS13Replacement of ADAM TS 13 activity2. FFP and cryosupernatant3. Glucocorticoids Pred 1-2 mg/kd/dMethylPred 1g/d for 3 days4. CsA, CTX5. Vincristine6. Rituximab7. Splenectomy Therapy: HUSSupportiveRRT for anuria over 24hPlasma e

10、xchange and FFP binant H factorPrudent Abx use (Abx can increase the release of Shiga toxin from E.coli O157:H7)Therapy Target: Remission PLT 150,000/L for 2 days : stop PE and begin to taper GCS dosage.Remission: nl PLT for 30 days after discontinuation of PE.Monitoring relapse: CBC, Blood smear, S

11、x and SnGuidelines and mendationsAABB and ASA (2003)Plasma exchange ASAP, with replacement of 1.0-1.5 times the predicted plasma volume till 2 days after PLT return to nl level.GCS should be added.No need to measure ADAM TS13 activity.Blood smear is ESSENTIAL! mended articleBarbara J. Bain , Diagnos

12、is from the Blood Smear. N Engl J Med 2005;353:498-507TTP and SLETTP: a rare complication of SLEAntiphospholipid antibody and LAintrinsic coagulopathy endothelial activation and damage thrombus formationAntibody to ADAM TS13 multimers of vWFTMASLE and TTP-HUS7/353 (2.0%), 27y/o (18-53), F: M =6:1 5

13、itantly; 1 SLETMA; 1 TMASLESLEDAI 20 (15-36)CM: ARF risk , prognosis (mortality 25-34%)ADAM TS13 antibody , returns to nl after TTP-HUS remission ADAM TS13 Ab plays an important role in pathogenesis of TTP associated with LN.Rx: Plasma therapy and Glucocorticoids Plasma exchange, FFP and cryosuperna

14、tant Lupus nephritis combined with renal injury due to thrombotic thrombocytopaenic purpura-haemolytic uraemic syndrome Feng Yu, Ying Tan and Ming-Hui Zhao Nephrol Dial Transplant (2010) 25: 145152News updateEremina V, Jefferson JA, Kowalewska J, et al. VEGF Inhibition and Renal Thrombotic Microangi

15、opathy, N Engl J Med 2008;358:1129-36.ConclusionProduction of VEGF by podocytes is required for health and maintenance of the adjacent glomerular endothelium.Thrombotic microangiopathy in patients who are treated with bevacizumab results from a reduction in glomerular VEGF, a direct, on-target effect of the drug.References George JN, Thrombotic thrombocytopenia purpura, N Engl J Med 2006;354:1927-35Moake JL, Thrombotic microangiopathies, N Engl J Med 2002; 347: 589-600Mayer SA, Aledort LM, Thrombotic microangiopathies: differential diagnsis, pathophysiology and therapeutic strategies, The mou