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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 ; 20 16-02-23. 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; 2016-02-23

  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) • Immun (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, szül: 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 • Retikulocytes 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. Complexity of the diagnosis: thrombotic microangiopathy (TMA) • Goal: the right patient should receive the right therapy in due time • Considerations on: • Timeline (acute-remission-relapse-long term management) • Therapy decisions (acute-upfront; remission-conclusive; relapse-prevention) • Alternate causes (definitive TMA, probable TMA, possible TMA) • Risks of therapy (infants, gestation, peri- or post tx) • Implementation/Access to therapy (PI, PEX, eculizumab)

  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: 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.

  8. 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

  9. 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

  10. www.eurosurveillance.org

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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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

  17. 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

  18. The cause of TTP are 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

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

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

  21. 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

  22. 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

  23. 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

  24. Illustrative cases, summary

  25. 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

  26. Illustrative cases, summary

  27. 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

  28. 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 • aHUS (factor deficient or autoimmune) • TTP (ADAMTS13 deficient with or without autoantibodies) • 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

  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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