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Pathogenesis and d ifferential diagnosis of thrombotic microangiopathies

Pathogenesis and d ifferential diagnosis of thrombotic microangiopathies. Zoltán Prohászka Research Laboratory, IIIrd Department of Medicine, Semmelweis University, Budapest prohoz@kut.sote.hu ; 2018-03-07. Classification of anemia according to etiology. Decreased production.

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Pathogenesis and d ifferential diagnosis of thrombotic microangiopathies

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  1. Pathogenesis and differential diagnosis of thrombotic microangiopathies Zoltán Prohászka Research Laboratory, IIIrd Department of Medicine, Semmelweis University, Budapest prohoz@kut.sote.hu; 2018-03-07

  2. Classification of anemia according to etiology Decreased production Loss of blood Hemolysis • Iron deficient • Megaloblastic • Cobalamin (B12) • Folic acid • Other forms • Anemia of chronic diseases • (kidney, hepar, cardiac…) • Morrow infiltration • Aplastic anemia • Various rare forms • Acute • Chronic • Membrane defect • Herediter spherocytosis • Herediter elliptocytosis • Paroxysmalis nocturnalis hemoglobinuria (PNH) • Hemoglobinopathies • Sickle cell disease • Thalassemia • metabolic changes • G6PD, PKD, other • Acquired, extrinsic • Intoxication (pl. plummet) • Physical (heat, trauma, vessel malformation, mechanic valves, paravalvular leaks) • Microangiopathic hemolysis • Infection (mycoplasma, clostridium) • Immune (auto-, iso-, drug)

  3. History >> physical examination >>Laboratory differentialdiagnosis of anemias(<complete blood count, urine, clincal chemistry, blood film, morrow, others>) Microcyter Normocyter Macrocyter • Iron deficiency • Anemia of chronic diseases • Thalassemia • Sideroblastic an. • Morrow OK • Blood production in morrow depressed • Megaloblastic • Non-megaloblastic

  4. L. Dóra, born: 1988 • History and family history negative, no medication. • Weakness, palpitation, headache since 5 days. No fever, no bleeding. • Pallor,P 100/min, suffusions on skin Complete blood count • WBC 7,16 G/L (12% Mo) • RBC 1,64 T/L • HGB 53 g/L • HCT 0,16 • MCV 95 fL • MCH 32 pg • MCHC 338 g/L • PLT 23 G/L • RDW-CV 23,2%

  5. L. Dóra, born: 1988 • History and family history negative, no medication. • Weakness, palpitation, headache since 5 days. No fever, no bleeding. • Pallor,P 100/min, suffusions on skin Complete blood count Bone morrow? Clincal chemistry • WBC 7,16 G/L (12% Mo) • RBC 1,64 T/L • HGB 53 g/L • HCT 0,16 • MCV 95 fL • MCH 32 pg • MCHC 338 g/L • PLT 23 G/L • Reticulocytes 296 G/L • Total bilirubine 33,7 umol/L • Indirect bi 8,6 • Crea 60 umol/L • GOT 56 U/L • GPT 142 U/L • LDH 1714 U/L • Hapltoglobin 0,1 g/L • Blood film: fragmentocytes • d. Coombs: neg.

  6. Intravasal hemolysis with fragmentocytes, Coombs-negative Laboratory signs: increased LDH, decreased hemoglobin and haptoglobin, free plasma hemoglobin, increase of indirect bilirubine Low platelet-count Exclusion of EDTA-induced decrease of platelet number, Verified by investigation of blood-smear Various presence of clinical signs: Various neurological symptomps Acute renal failure Other No requirement of fever HUS: Hemolytic uremic syndrome TTP: Thrombotic thrombocytopenic purpura Initial, clinical diagnosis of HUS/TTP syndrome, i.e. thrombotic microangiopathies(hospital day 1) www.med-ed.virginia.edu/courses/path/innes/images/rcdjpegs/rcd Slide thanks to Dr. Kline Bolton, UVA.

  7. Intravasal hemolysis with fragmentocytes, Coombs-negative Laboratory signs: increased LDH, decreased hemoglobin and haptoglobin, free plasma hemoglobin, increase of indirect bilirubine Low platelet-count Exclusion of EDTA-induced decrease of platelet number, Verified by investigation of blood-smear Various presence of clinical signs: Neurological or renal No requirement of fever Simplified classification of HUS/TTP (1-2) Infection-related HUS EHEC D+HUS ‘typical’ Initial, clinical diagnosis of HUS/TTP syndrome (hospital day 1) • Besbas et al, 2006, Kidney International • Ariceta et al, 2009, Pediatric Nephrology

  8. Predisposition, direct cause of disease Acute disease episode, hemolysis, thrombocytopenia Complication, outcome D+HUS Shiga-like toxin producing bacteria, gastroenteritis Rarely Clinical course of thrombotic microangiopathies (HUS/TTP syndrome) aHUS P-HUS TTP (Moschcowitz sy) Congenital TTP (Upshaw-Schulman sy) Secondary HUS/TTP

  9. www.eurosurveillance.org

  10. Numbers of diarrhea positive and HUS cases over time (2011) Peak of exposition Frank C, NEJM 2011; Jun 22

  11. Intravasal hemolysis with fragmentocytes, Coombs-negative Laboratory signs: increased LDH, decreased hemoglobin and haptoglobin, free plasma hemoglobin, increase of indirect bilirubine Low platelet-count Exclusion of EDTA-induced decrease of platelet number, Verified by investigation of blood-smear Various presence of clinical signs: Neurological or renal No requirement of fever Simplified classification of HUS/TTP (1-2) Infection-related HUS EHEC D+HUS PneumococcusP-HUS Influenza Neur-HUS Complement-related HUS Mutations aHUS, factor deficient Autoimmune anti-FH positive ADAMTS13 deficient TTP Autoimmune anti-ADAMTS13 pos Mutations Upshaw-Schulman sy Secondary forms, other rare entity Initial, clinical diagnosis of HUS/TTP syndrome (hospital day 1) • Besbas et al, 2006, Kidney International • Ariceta et al, 2009, Pediatric Nephrology

  12. Predisposition, direct cause of disease Acute disease episode, hamolysis, thrombocytopenia Complication, outcome D+HUS Shiga-like toxin producing bacteria, gastroenteritis Rarely Clinical course of thrombotic microangiopathies (HUS/TTP syndrome) aHUS Complement deficiency (Mutation, autoantibody) ESRD, dialysis, tx P-HUS TTP (Moschcowitz sy) Congenital TTP (Upshaw-Schulman sy) Secondary HUS/TTP

  13. Simplified schema of the complement system Classical pathway (Immune complexes) Alternative pathway (Spontaneous C3 activation) Factor B and Factor D C3 activation Regulators: C1-inhibitor, C4-binding protein, Factor I Regulators: MCP, DAF, Factor H and Factor I Lectin pathway (Carbohydrate structures) Alternative pathway amplification C3bBbP Opsonization Antigen presentation Antibody production C5 activation Regulators: CD59, S protein and Clusterin Anaphylatoxins C3a, C5a Inflammation Chemotaxis C5-C9 Terminal Pathway • Cascade • Activation: whole pathway • Missing regulation: characteristic picture Lysis Cellular damages Induction of apoptosis

  14. Simplified schema of the complement system Classical pathway (Immunecomplexes) Alternative pathway (Spontaneous C3 activation) Factor B and Factor D C3 activation Regulators: C1-inhibitor, C4-binding protein, Factor I Regulators: MCP, DAF, Factor H and Factor I Lectin pathway (Carbohydrate structures) Alternative pathway amplification C3bBbP Opsonization Antigen presentation Antibody production C5 activation Regulators: CD59, S protein and Clusterin Anaphylatoxins C3a, C5a Inflammation Chemotaxis C5-C9 Terminal Pathway Lysis Cellular damages Induction of apoptosis

  15. Pathogenesis of complement mediated atypical HUS • Predisposition, rare genetic variants • Mutations of complement alternative pathway regulators (CFH>MCP>CFI>>THMB>CFB>C3>CFHR5>others) • Predisposition, frequent genetic variants („complotype”) • Haplotypes • CFH H3/H8 • MCPggaac • Copy-number variations • CFHR1-3 deletion • Predisposition, autoantibodies • Development of anti-Factor H autoantibodies, based on genetic predisposition (CFHR1 deletion) • Direct disease-precipitating trigger • Infections • Pregnancy

  16. Predisposition, direct cause of disease Acute disease episode, hamolysis, thrombocytopenia Complication, outcome D+HUS Shiga-like toxin producing bacteria, gastroenteritis Rarely Clinical course of thrombotic microangiopathies (HUS/TTP syndrome) aHUS Complement deficiency (Mutation, autoantibody) ESRD, dialysis, tx P-HUS Invasive pneumococcus infection ? DR11/DQ3 haplotype Anti-ADAMTS13 TTP (Moschcowitz sy) Neurological defect ADAMTS13 mutation Congenital TTP (Upshaw-Schulman sy) Neurological defect Secondary HUS/TTP ? Underlying disease, if treatable, good outcomes

  17. The cause of TTP is the pro-coagulant changes of in microvessels • ADAMTS13 metalloprotease cleaves von Willebrand Factor to small (4-6-8) oligomers • In case of ADaMTS13 deificency ultralarge vWF multimers remain attached to the endothelial surface • ADAMTS13 deficiency may be related to • Mutation of ADAMTS13 (congenital form, ultrare, Upshaw-Schulman sy) • Autoantibodies (acquired form, Moschcowitz sy, most frequent) • Consumption

  18. The cause of TTP is the pro-coagulant changes of in microvessels • Ép funkció ADAMTS13 non-processed ULVWF processed oligomers

  19. ADAMTS13 damage ADAMTS13 mutation ADAMTS13 inhibitory autoantibody Y Thrombocyta adhesion Thrombocyta activation Thrombocyta degranulation ULVWF Thrombocyta aggregation Thrombus Endothel- activation Complement- activation

  20. Case #1 (BSI, HUN59) 37 y old female, no major diseases Abdominal pain, nasal bleeding and headache On the day of hospitalization coma, focal neurological signs Intracranial bleeding (pons) Se Bi: 21 umol/L, WBC 21 G/L, Hgb 93 g/L, Plt 3 G/L, Crea 295 umol/L, LDH 278 U/mL Plasmapheresis and SoluMedrol therapy initiated, working diagnosis: HUS/TTP syndrome Case #2 (BI, HUN238) 46 y old male, no major diseases Abdominal pain, vomiting and non-bloody diarrhea, dark urine On the day of hospitalization oliguria, increased creatinine and BUN levels Se Bi: 46 umol/L, WBC 10 G/L, Hgb 103 g/L, Plt 2 G/L, Crea 408 umol/L, LDH 4161 U/mL EHEC testing negative Plasmapheresis and SoluMedrol therapy initiated, working diagnosis: HUS/TTP syndrome Illustrative cases, adults

  21. Case #3 (MZ HUN1) 21 y old female with first uncomplicated pregnancy until week 40 HELLP syndrome, urgent cesarean section Se Bi: 72 umol/L, WBC 11 G/L, Hgb 65 g/L, Plt 35 G/L, Crea 54 umol/L, LDH 990 U/mL Critical clinical status despite plasmapheresis, corticosteroids Revision of diagnosis: HUS/TTP? Case #4 (MN HUN246) 20 y old female with first uncomplicated pregnancy Postpartum HUS syndrome Renal biopsy: TMA Severe hypertension, encephalopathy Plasmapheresis (26 sessions), corticosteroid, rituximab Illustrative cases, peripartum

  22. Case #5 (GL HUN193) 8 months old boy Pallor, weakness, no fever, no diarrhea Hgb 62 g/L, Plt 42 G/L, WBC 11 G/L, Crea 196 umol/L, LDH 4250 U/mL Critical clinical status, worsening renal and heart function Multiple plasma infusions, Initial diagnosis: HUS Case #6 (KM HUN200) 8 y old boy Weakness, vomiting, abdominal pain, icterus, dark urine, no fever, no diarrhea Hgb 106 g/L, Plt 44 G/L, WBC 7,8 G/L, Crea 159 umol/L, LDH 4300 U/mL, EHEC testing negative Stable clinical status Multiple plasma infusions and plasmapheresisInitial diagnosis: HUS Illustrative cases, children

  23. Illustrative cases, summary

  24. Initial, life-threatening therapy • PE with FFP is still the most effective treatment available for TTP (1) • Rituximab (or cyclophosphamide) is indicated for patients with chronic relapsing disease (autoimmune) • Anti-platelet therapy and immunosuppression may also be considered • For HUS, most of the RCTs focused on typical HUS and showed that supportive therapy including dialysis is still the most effective treatment (1) • The „Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome” article indicates initiation of PE with FFP in the first 24 hours (2) • Eculizumab can be considered for proven cases of complement-mediated aHUS • Pulse cyclophosphamid and rituximab can be considered for anti-FH autoantibody mediated aHUS • Michael et al, The Cochrane Library 2009, Issue 1 • Ariceta et al, 2009, Ped Nephrol

  25. Illustrative cases, summary

  26. Therapeutic dilemma on day ~3-6 • Judgment of initial response to plasma therapy, steroids • Results of initial laboratory testing, exclusion of: • Sepsis, DIC • Anti-phospholipid syndrome and SLE • Other causes of hemolysis and low platelet numbers • Secondary HUS/TTP

  27. Therapeutic dilemma on day ~3-6 Failing or insufficient • Judgment of initial response to plasma therapy, steroids • Results of initial laboratory testing, exclusion of: • Sepsis, DIC • Anti-phospholipid syndrome and SLE • Other causes of hemolysis and low platelet numbers • Secondary HUS/TTP • Where next with HUS/TTP on hospital day 3-6? • Is there a reliable laboratory test to classify patients into the following groups in a short time? • D+HUS • TTP (ADAMTS13 deficient with or without autoantibodies) • aHUS (factor deficient or autoimmune) • How to decide? • Intensify immunosuppression (Cy, R) for autoimmune disease (Ab+ aHUS, Ab+TTP)? • Intensify factor supply/ targeted inhibition of complement (factor deficient TTP or aHUS)? No alternative diagnosis

  28. Which are the useful clinical or laboratory markers to differentiate clinical TMA syndromes in the first days of hospital care? • Urgent testing of ADAMTS13 activity (samples taken before therapy) • ADAMTS13 deficiency (0-10%): TTP • ADAMTS13 decrease(10-60%: TMA (but not TTP) • ADAMTS13 in referent range (60-150%): Careful watching, follow up • If ADAMTS13 activity measurment is not available: • Store samples! • Decision by clinical signs: • If creatinine<200 umol/L, and PLT<30 G/L and ANA pos…..than 98,7% chance, that thepatient has ADAMTS13 is deficiency Results of Laboratory Testing in 214 Patients with Thrombotic Microangiopathy According to ADAMTS13 Activity. P Coppo et al, 2010, PLOS One

  29. Guideline for the investigation of aHUS (1) • Clinical recognition of aHUS • No recent diarrhea • Recent diarrhea but any one of the following • Age <6months • Insidious onset • Relapse of HUS • Suspected previous HUS • Previous unexplained anaemia • HUS post-transplantation of any organ • Asynchronous family history of HUS • Laboratory recognition of aHUS • Complement C3 • Complement FI and FH • Anti-FH autoantibody • MCP (CD46) surface expression • Genetic analysis (CFH, CFI, CD46, CFB, C3, THBD2) • Exclusion of TTP • ADAMTS13 activity measurement • Anti-ADAMTS13 autoantibody determination (1) Ariceta et al, 2009, Ped Nephrol

  30. Illustrative cases, summary

  31. Suggestions for diagnostic testing of patients with suspicion of TMA • Hospital day 1: verification of intravasal hemolysis and low platelet count, blood smear, differential-diagnosis. • Hospital day 2-5: Before plasmapheresis initiation of detailed complement and ADAMTS13 testing • Identification of AP over-activation and consumption, anti-FH IgG • ADAMTS13 deficiency • Within 1-2 months: Detailed complement investigations • Identification of missing complement factor(s) • Genetic analysis

  32. Photo: Kata Tolnai Coworkers of the Füst György Komplement Diagnosztikai Laboratórium www.kutlab.hu CEE Roundtable discussion, Zoltan Prohaszka 23-10-2014

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